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Point and Counterpoint |

POINT: Should Patients Receiving Statins Prior to ICU Admission Be Continued on Statin Therapy? YesContinued Statins in ICU? Yes FREE TO VIEW

Alexander H. Flannery, PharmD, BCPS; Peter S. Kruger, MBBS, PhD
Author and Funding Information

From the Medical Intensive Care Unit/Pulmonary (Dr Flannery), College of Pharmacy, University of Kentucky HealthCare; Intensive Care (Dr Kruger), Princess Alexandra Hospital, Woolloongabba; and Discipline of Anaesthesiology and Critical Care (Dr Kruger), University of Queensland.

CORRESPONDENCE TO: Alexander H. Flannery, PharmD, BCPS, University of Kentucky HealthCare, 800 Rose St, H110, Lexington, KY 40536; e-mail: alex.flannery@uky.edu


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(6):1431-1433. doi:10.1378/chest.14-2223
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Published online

With the release of updated guidelines for the treatment of cholesterol, an additional 13 million Americans may be eligible for or prescribed statin therapy, possibly bringing the overall total to 56 million.1,2 Already, as many as 30% of acute hospital admissions are prescribed statins.3 More patients than ever before are likely to present to the hospital receiving statins prior to admission, making the decision to continue a patient’s home statin regimen an almost daily occurrence for practicing critical care physicians. Unintentional discontinuation of medications for chronic disease is a risk with hospitalization and an even greater risk with ICU admission.4 As such, the clinical question related to continued statin therapy in the ICU provides an opportunity to influence both short- and long-term outcomes from critical illness.

The best-known mechanism of action for statins involves inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The inhibition of mevalonate synthesis explains the primary effect of statins to reduce cholesterol levels, but it also offers an explanation of the pleiotropic effects of statins that are perhaps independent of cholesterol. Inhibition of mevalonate synthesis may inhibit the activation of guanosine triphosphate-binding proteins, thereby reducing the activation of transcription factors and resulting in the pleiotropic (ie, antiinflammatory, antioxidant, immune modulation, antithrombotic, protection of endothelial function) effects of statins.5

Acute discontinuation of statin therapy has been postulated to influence outcomes in a variety of illnesses, although much of this is only supported by observational data. For patients with acute coronary syndrome, withdrawal of preexisting statin therapy has been associated with a worse outcome.6 Data for this analysis were from a study where clinical decisions regarding statin use were not part of the original study protocol. Although this creates a potential bias that usual medications, including statin therapy, were ceased in more unwell patients, it is interesting that the cessation of prior statin use was associated with a worse outcome than no prior use or continued use. Additionally, a small randomized trial of patients with stroke suggested an improved outcome when prior statin therapy was continued.7 Statin withdrawal has also been associated with an increased risk for adverse cardiovascular events following vascular surgery.8

The most extensive body of literature on the role of statins in critical care has focused on patients with sepsis. Although the benefits of de novo statin therapy for treating sepsis in the ICU remain investigational, the number of reports describing a beneficial effect of continuing a patient’s statin prescription continues to emerge. A 2006 retrospective cohort study using multivariate regression analysis suggested that continued use of a patient’s outpatient statin therapy is an independent predictor of hospital mortality.9 A similar suggestion of mortality benefit was described in candidemia.10

In a nested cohort study within two randomized controlled trials, statin use in the ICU, most of which was continued from the patient’s outpatient regimen, was associated with a reduction in hospital mortality, particularly for doses of atorvastatin or simvastatin ≥ 40 mg.11 In a 6-year French cohort study investigating prior statin therapy on the impact of ventilator-associated pneumonia, statin continuation after ICU admission was an independent predictor of 30-day mortality.12 Although a similar retrospective analysis has demonstrated that the benefits of continuing statin therapy in the ICU disappear after propensity matching and multivariate adjustment, there still appears to be a trend toward benefit in this analysis, with statistical significance limited by small sample size.13

Perhaps the two most intriguing and conflicting studies are the randomized controlled trials investigating this clinical issue. In a phase 2 multicenter, prospective, randomized, double-blind, placebo-controlled trial, subjects were stratified by site as well as by prior statin use to atorvastatin 20 mg daily or matching placebo.14 Although de novo statin therapy was not associated with either attenuation of infection or improved survival, benefits were observed in the prior statin user group. Prior statin users were noted to have lower levels of IL-6 at baseline. Additionally, prior statin users randomized to continued statin therapy in the ICU demonstrated a lower 28-day mortality than those who discontinued statin therapy upon ICU admission.

In a prospective, randomized, double-blind, placebo-controlled trial, 150 patients on prior statin therapy hospitalized for infection were randomized to atorvastatin 20 mg or placebo.3 No significant differences were found between the two study groups over time in any of the outcomes, including levels of IL-6 and C-reactive protein, degree of organ failure, and mortality. Of note, only 16% of the cohort required ICU care, and the overall cohort had a low mortality of 6.6% compared with the previously mentioned study whose patients were critically ill with APACHE (Acute Physiology and Chronic Health Evaluation) II scores ranging from 21.2 to 25.6.14 It is possible that the pleiotropic effects of statins may not be fully appreciated unless marked systemic inflammation is present, potentially explaining the lack of benefit observed in general ward patients compared with more unwell patients.

Continued statin use in the ICU may have other benefits due to its association with reductions in delirium. Statins may alter the neuroinflammatory process, which is hypothesized to contribute to ICU delirium. For every day that statin use is continued in the ICU, the odds of the patient being delirium and coma free increases by 39%.15 A recent multicenter, prospective cohort study revealed that the probability of delirium increases the longer a patient remains off his or her home statin regimen.16

The prospective studies evaluating statin use for a variety of ICU conditions have vigilantly screened for adverse effects, such as elevation in hepatocellular enzyme and creatine kinase levels. With one exception, they have consistently found no significant differences compared with placebo.3,14,17-19 Combined, this represents safety data on statin use in the ICU for almost 800 patients. The exception is the recently completed study of rosuvastatin in ARDS.19 Although no differences were found between the rosuvastatin and placebo groups in significant elevation of creatine kinase or alanine aminotransferase levels, the protocol was amended during the study for closer aspartate aminotransferase monitoring. Elevated aspartate aminotransferase levels were subsequently found to be more common in patients receiving rosuvastatin than in those receiving placebo, although the numbers were small. The clinical significance of this finding remains unclear and stands in contrast to the multiple studies that failed to suggest any safety concerns with statin use in the ICU. Although drug levels of statins in the critically ill have been reported in some but not all cases to be well in excess of healthy volunteers, this finding has not led to an overt suggestion that statin use in the ICU is unsafe.13,19,20 It remains unknown whether these elevated concentrations explain the improved outcomes in patients on continued statin therapy in the ICU.14 Statins take 7 to 14 days to reach peak antiinflammatory effects, potentially explaining why there appears to be a larger benefit for continuing as opposed to de novo statin therapy.5

Limited information exists regarding the current state of practice of continuing a patient’s home statin therapy upon ICU admission. In a 2012 international survey of physicians in Australia, New Zealand, and the United Kingdom, 77.4% of physicians responded that they would restart a patient’s statin therapy during ICU admission, even if no new cardiac indications were present.21

Further randomized trials are needed to confirm the risk-benefit ratio of continuing statin therapy in the ICU. The suggestion of benefit across a variety of outcomes without an apparent increase in adverse effects and the low cost of therapy favor continuation while more definitive evidence is gathered.

Abbreviations

ACS

acute coronary syndrome

ALT

alanine aminotransferase

ARDSNet

ARDS Clinical Trial Network

AST

aspartate aminotransferase

Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370(15):1422-1431. [CrossRef] [PubMed]
 
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25)(suppl 2):S1-S45. [CrossRef] [PubMed]
 
Kruger PS, Harward ML, Jones MA, et al. Continuation of statin therapy in patients with presumed infection: a randomized controlled trial. Am J Respir Crit Care Med. 2011;183(6):774-781. [CrossRef] [PubMed]
 
Bell CM, Brener SS, Gunraj N, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chronic diseases. JAMA. 2011;306(8):840-847. [CrossRef] [PubMed]
 
De Loecker I, Preiser JC. Statins in the critically ill. Ann Intensive Care. 2012;2(1):19. [CrossRef] [PubMed]
 
Heeschen C, Hamm CW, Laufs U, Snapinn S, Böhm M, White HD; Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002;105(12):1446-1452. [CrossRef] [PubMed]
 
Blanco M, Nombela F, Castellanos M, et al. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology. 2007;69(9):904-910. [CrossRef] [PubMed]
 
Schouten O, Hoeks SE, Welten GM, et al. Effect of statin withdrawal on frequency of cardiac events after vascular surgery. Am J Cardiol. 2007;100(2):316-320. [CrossRef] [PubMed]
 
Kruger P, Fitzsimmons K, Cook D, Jones M, Nimmo G. Statin therapy is associated with fewer deaths in patients with bacteraemia. Intensive Care Med. 2006;32(1):75-79. [CrossRef] [PubMed]
 
Forrest GN, Kopack AM, Perencevich EN. Statins in candidemia: clinical outcomes from a matched cohort study. BMC Infect Dis. 2010;10:152. [CrossRef] [PubMed]
 
Al Harbi SA, Tamim HM, Arabi YM. Association between statin therapy and outcomes in critically ill patients: a nested cohort study. BMC Clin Pharmacol. 2011;11:12. [CrossRef] [PubMed]
 
Bruyere R, Vigneron C, Prin S, et al. Impact of prior statin therapy on the outcome of patients with suspected ventilator-associated pneumonia: an observational study. Crit Care. 2014;18(2):R83. [CrossRef] [PubMed]
 
Mekontso Dessap A, Ouanes I, Rana N, et al. Effects of discontinuing or continuing ongoing statin therapy in severe sepsis and septic shock: a retrospective cohort study. Crit Care. 2011;15(4):R171. [CrossRef] [PubMed]
 
Kruger P, Bailey M, Bellomo R, et al; 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;187(7):743-750. [CrossRef] [PubMed]
 
Page VJ, Davis D, Zhao XB, et al. Statin use and risk of delirium in the critically ill. Am J Respir Crit Care Med. 2014;189(6):666-673. [CrossRef] [PubMed]
 
Morandi A, Hughes CG, Thompson JL, et al. Statins and delirium during critical illness: a multicenter, prospective cohort study. Crit Care Med. 2014;42(8):1899-1909. [CrossRef] [PubMed]
 
Papazian L, Roch A, Charles PE, et al; STATIN-VAP Study Group. Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial. JAMA. 2013;310(16):1692-1700. [CrossRef] [PubMed]
 
Craig TR, Duffy MJ, Shyamsundar M, et al. A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med. 2011;183(5):620-626. [CrossRef] [PubMed]
 
Truwit JD, Bernard GR, Steingrub J, et al; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014;370(23):2191-2200. [CrossRef] [PubMed]
 
Kruger PS, Freir NM, Venkatesh B, Robertson TA, Roberts MS, Jones M. A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis. Intensive Care Med. 2009;35(4):717-721. [CrossRef] [PubMed]
 
Shankar-Hari M, Kruger PS, Di Gangi S, et al. Statin therapy in critical illness: an international survey of intensive care physicians’ opinions, attitudes and practice. BMC Clin Pharmacol. 2012;12:13. [CrossRef] [PubMed]
 

Figures

Tables

References

Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370(15):1422-1431. [CrossRef] [PubMed]
 
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25)(suppl 2):S1-S45. [CrossRef] [PubMed]
 
Kruger PS, Harward ML, Jones MA, et al. Continuation of statin therapy in patients with presumed infection: a randomized controlled trial. Am J Respir Crit Care Med. 2011;183(6):774-781. [CrossRef] [PubMed]
 
Bell CM, Brener SS, Gunraj N, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chronic diseases. JAMA. 2011;306(8):840-847. [CrossRef] [PubMed]
 
De Loecker I, Preiser JC. Statins in the critically ill. Ann Intensive Care. 2012;2(1):19. [CrossRef] [PubMed]
 
Heeschen C, Hamm CW, Laufs U, Snapinn S, Böhm M, White HD; Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Investigators. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002;105(12):1446-1452. [CrossRef] [PubMed]
 
Blanco M, Nombela F, Castellanos M, et al. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology. 2007;69(9):904-910. [CrossRef] [PubMed]
 
Schouten O, Hoeks SE, Welten GM, et al. Effect of statin withdrawal on frequency of cardiac events after vascular surgery. Am J Cardiol. 2007;100(2):316-320. [CrossRef] [PubMed]
 
Kruger P, Fitzsimmons K, Cook D, Jones M, Nimmo G. Statin therapy is associated with fewer deaths in patients with bacteraemia. Intensive Care Med. 2006;32(1):75-79. [CrossRef] [PubMed]
 
Forrest GN, Kopack AM, Perencevich EN. Statins in candidemia: clinical outcomes from a matched cohort study. BMC Infect Dis. 2010;10:152. [CrossRef] [PubMed]
 
Al Harbi SA, Tamim HM, Arabi YM. Association between statin therapy and outcomes in critically ill patients: a nested cohort study. BMC Clin Pharmacol. 2011;11:12. [CrossRef] [PubMed]
 
Bruyere R, Vigneron C, Prin S, et al. Impact of prior statin therapy on the outcome of patients with suspected ventilator-associated pneumonia: an observational study. Crit Care. 2014;18(2):R83. [CrossRef] [PubMed]
 
Mekontso Dessap A, Ouanes I, Rana N, et al. Effects of discontinuing or continuing ongoing statin therapy in severe sepsis and septic shock: a retrospective cohort study. Crit Care. 2011;15(4):R171. [CrossRef] [PubMed]
 
Kruger P, Bailey M, Bellomo R, et al; 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;187(7):743-750. [CrossRef] [PubMed]
 
Page VJ, Davis D, Zhao XB, et al. Statin use and risk of delirium in the critically ill. Am J Respir Crit Care Med. 2014;189(6):666-673. [CrossRef] [PubMed]
 
Morandi A, Hughes CG, Thompson JL, et al. Statins and delirium during critical illness: a multicenter, prospective cohort study. Crit Care Med. 2014;42(8):1899-1909. [CrossRef] [PubMed]
 
Papazian L, Roch A, Charles PE, et al; STATIN-VAP Study Group. Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial. JAMA. 2013;310(16):1692-1700. [CrossRef] [PubMed]
 
Craig TR, Duffy MJ, Shyamsundar M, et al. A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med. 2011;183(5):620-626. [CrossRef] [PubMed]
 
Truwit JD, Bernard GR, Steingrub J, et al; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014;370(23):2191-2200. [CrossRef] [PubMed]
 
Kruger PS, Freir NM, Venkatesh B, Robertson TA, Roberts MS, Jones M. A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis. Intensive Care Med. 2009;35(4):717-721. [CrossRef] [PubMed]
 
Shankar-Hari M, Kruger PS, Di Gangi S, et al. Statin therapy in critical illness: an international survey of intensive care physicians’ opinions, attitudes and practice. BMC Clin Pharmacol. 2012;12:13. [CrossRef] [PubMed]
 
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