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Point and Counterpoint |

COUNTERPOINT: Should Patients Receiving Statins Prior to ICU Admission Be Continued on Statin Therapy? NoContinued Statins in ICU? No FREE TO VIEW

Joel D. Mermis, MD; Steven Q. Simpson, MD, FCCP
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine, University of Kansas School of Medicine.

CORRESPONDENCE TO: Steven Q. Simpson, MD, FCCP, Division of Pulmonary and Critical Care Medicine, University of Kansas School of Medicine, 3901 Rainbow Blvd, Mail Stop 3007, Kansas City, KS 66160; e-mail: ssimpson3@kumc.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):1433-1435. doi:10.1378/chest.14-2225
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For every patient admitted to an ICU, providers must make crucial decisions regarding which medications to use to enhance the patient’s likelihood of survival and long-term recovery. Sometimes the decision is only regarding which medications to initiate in the ICU. However, we often must decide which outpatient medications are crucial or desirable to continue in the ICU and which are either not helpful or detrimental to the patient’s current condition. Among the most common drugs that force this decision are the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, commonly known as statins. Statins are the best selling and most widely used agents in the history of the pharmaceutical industry, and many patients admitted to the ICU with a critical illness have been taking these drugs as outpatients.1 We believe that for most critical illnesses, there is insufficient evidence to warrant continuation of treatment with statins in the ICU setting. To address this issue as a risk analysis proposition, we pose a series of important questions.

Statins exhibit numerous properties in in vitro and in animal experiments that suggest a role for the drugs in the treatment or prevention of critical illnesses.2 They alter synthesis and release of inflammatory cytokines through several mechanisms, alter leukocyte rolling and adhesion, inhibit inducible nitric oxide synthase, and inhibit microvascular clotting. It is mechanistically plausible that statins could benefit critically ill patients. Unfortunately, no high-quality evidence is available that statins are beneficial in any human critical illness, save acute coronary syndrome (ACS). Early observational studies suggested that statins improve outcomes in certain common critical conditions, such as pneumonia, sepsis, and ARDS.3-5 However, randomized trials in a variety of critical illnesses have failed to demonstrate benefit, whether statins were initiated on admission or continued in patients who were already taking them in the outpatient setting.6,7 The ARDS Clinical Trial Network (ARDSNet) recently published the largest randomized trial to date (745 patients) evaluating the safety and efficacy of statins in sepsis-induced ARDS.8 Unfortunately, statins offered no survival benefit (rosuvastatin, 28.5%; placebo, 24.9%; P = .21).

The mechanism of action of statins suggests a possible role for the drugs in the primary prevention of inflammatory critical illnesses, such as severe sepsis or ARDS. However, the available evidence does not support a role for statins in primary prevention of critical illness. For patients with pneumonia or bloodstream infections, statin use does not protect against renal failure, ICU admission, or ventilator use, nor does it reduce length of stay or mortality.9,10 If the mechanisms whereby statins are proposed to both prevent and treat critical illness have been overcome and patients have become critically ill despite statin therapy, it is difficult to logically propose a mechanism whereby continued administration of the same medicine is likely to be successful, unless it is unsafe to discontinue the drug while a patient is critically ill. Even then, the drug must be safe to administer to a critically ill patient.

Concern regarding the safety of continuing statins in critically ill patients is logical because statins have demonstrated risk for harm in noncritically ill patients. Postmarketing reports have demonstrated risk of statin-induced myopathy and less often, severe liver injury, even in noncritically ill patients.11,12 Risk for myopathy appears greatest with higher-dose simvastatin and correlates with serum concentrations of the statin.11,13 Risk for potentially toxic serum levels is particularly increased in the 15% of the population that carries certain variants of the SLCO1B1 gene, which encodes the organic anion transporter polypeptides responsible for hepatocyte uptake of statins.13 Two studies examining the pharmacokinetics of statins in critically ill patients demonstrated that despite statin administration at normal doses, serum drug levels often become supratherapeutic.14,15 The authors surmised that increased serum statin concentrations in these critically ill patients were related to frequent concomitant use of other medications that affect cytochrome P450 metabolism, such as azoles, haloperidol, midazolam, and amiodarone. Of interest, the ARDSNet study Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome found that the median peak plasma level of rosuvastatin was actually below the intended target range.8 Rosuvastatin has less cytochrome P450 interaction than simvastatin or atorvastatin, and this likely explains the increased risk for toxic statin levels in patients taking the latter two drugs. Despite using a statin with less risk for myopathy and measuring lower-than-anticipated plasma levels, rosuvastatin treatment raised concern for toxicity because patients on treatment had significantly higher aspartate aminotransferase levels and fewer days free of hepatic and renal failure. Of the 109 patients in this study who were taking a statin prior to enrollment, continuation of a statin rather than placebo resulted in a nonstatistically significant 11% absolute increase in risk of death at 90 days. Although this study was not powered to specifically evaluate mortality in patients with sepsis on a prior statin, it raises concern that continuation may actually cause more harm than was previously recognized.

Studies have suggested a potential harm to stopping statins during an ACS.16 However, in the absence of an ACS, discontinuation of statins in stable cardiac patients for at least 6 weeks has been demonstrated to be safe.17 Existing reports suggested that statin discontinuation in critically ill patients is safe. In a retrospective analysis of 78 patients with severe sepsis or septic shock receiving statin , the 32 patients in whom statin treatment was discontinued at ICU admission did not have more organ failure.15 Furthermore, in a placebo-controlled trial of 250 patients with severe sepsis, 77 of whom were current users of statin, the placebo rather than continuation of atorvastin 20 mg did not result in a difference in hospital length of stay, Sequential Organ Failure Assessment score, 90-day mortality, or adverse events between the two groups.18 Additionally, there was no increase in adverse events reported in the 55 prior statin users in the ARDSNet study who received placebo instead of a statin.8 Discontinuation of statin in critically ill patients appears to be safe.

Like so many promising agents to treat critical illnesses, such as severe sepsis, statins have failed to meet the mark in tests of efficacy. They do not prevent the onset of inflammation-related critical illnesses, and they have no demonstrated efficacy to treat critical illnesses. However, the drugs have been demonstrated to cause harm to critically ill patients. Any drug that has demonstrated risks but no clear beneficial effect does not have a favorable risk-benefit profile. Available data do not support continuation of statins in critically ill patients.

Jackevicius CA, Chou MM, Ross JS, Shah ND, Krumholz HM. Generic atorvastatin and health care costs. N Engl J Med. 2012;366(3):201-204. [CrossRef] [PubMed]
 
Mermis JD, Simpson SQ. HMG-CoA reductase inhibitors for prevention and treatment of severe sepsis. Curr Infect Dis Rep. 2012;14(5):484-492. [CrossRef] [PubMed]
 
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;25(4):656.e7-656.22. [CrossRef]
 
Rothberg MB, Bigelow C, Pekow PS, Lindenauer PK. Association between statins given in hospital and mortality in pneumonia patients. J Gen Intern Med. 2012;27(3):280-286. [CrossRef] [PubMed]
 
O’Neal HRJ Jr, Koyama T, Koehler EA, et al. Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome. Crit Care Med. 2011;39(6):1343-1350. [CrossRef] [PubMed]
 
Patel J, Snaith C, Thickett D, et al. Atorvastatin for preventing the progression of sepsis to severe sepsis (ASEPSIS Trial): a randomised, double-blind, placebo-controlled trial (ISRCTN64637517). Crit Care. 2011;15(suppl 1):268. [CrossRef]
 
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]
 
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]
 
Murugan R, Weissfeld L, Yende S, Singbartl K, Angus DC, Kellum JA; Genetic and Inflammatory Markers of Sepsis (GenIMS) Investigators. Association of statin use with risk and outcome of acute kidney injury in community-acquired pneumonia. Clin J Am Soc Nephrol. 2012;7(6):895-905. [CrossRef] [PubMed]
 
Leung S, Pokharel R, Gong MN. Statins and outcomes in patients with bloodstream infection: a propensity-matched analysis. Crit Care Med. 2012;40(4):1064-1071. [CrossRef] [PubMed]
 
Egan A, Colman E. Weighing the benefits of high-dose simvastatin against the risk of myopathy. N Engl J Med. 2011;365(4):285-287. [CrossRef] [PubMed]
 
Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol. 2012;56(2):374-380. [CrossRef] [PubMed]
 
Link E, Parish S, Armitage J, et al; SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008;359(8):789-799. [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]
 
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]
 
Heeschen C, Hamm CW, Laufs U, Böhm M, Snapinn S, White HD. Withdrawal of statins in patients with acute coronary syndromes. Circulation. 2003;107(3):e27. [CrossRef] [PubMed]
 
McGowan MP; Treating to New Target (TNT) Study Group. There is no evidence for an increase in acute coronary syndromes after short-term abrupt discontinuation of statins in stable cardiac patients. Circulation. 2004;110(16):2333-2335. [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]
 

Figures

Tables

References

Jackevicius CA, Chou MM, Ross JS, Shah ND, Krumholz HM. Generic atorvastatin and health care costs. N Engl J Med. 2012;366(3):201-204. [CrossRef] [PubMed]
 
Mermis JD, Simpson SQ. HMG-CoA reductase inhibitors for prevention and treatment of severe sepsis. Curr Infect Dis Rep. 2012;14(5):484-492. [CrossRef] [PubMed]
 
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;25(4):656.e7-656.22. [CrossRef]
 
Rothberg MB, Bigelow C, Pekow PS, Lindenauer PK. Association between statins given in hospital and mortality in pneumonia patients. J Gen Intern Med. 2012;27(3):280-286. [CrossRef] [PubMed]
 
O’Neal HRJ Jr, Koyama T, Koehler EA, et al. Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome. Crit Care Med. 2011;39(6):1343-1350. [CrossRef] [PubMed]
 
Patel J, Snaith C, Thickett D, et al. Atorvastatin for preventing the progression of sepsis to severe sepsis (ASEPSIS Trial): a randomised, double-blind, placebo-controlled trial (ISRCTN64637517). Crit Care. 2011;15(suppl 1):268. [CrossRef]
 
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]
 
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]
 
Murugan R, Weissfeld L, Yende S, Singbartl K, Angus DC, Kellum JA; Genetic and Inflammatory Markers of Sepsis (GenIMS) Investigators. Association of statin use with risk and outcome of acute kidney injury in community-acquired pneumonia. Clin J Am Soc Nephrol. 2012;7(6):895-905. [CrossRef] [PubMed]
 
Leung S, Pokharel R, Gong MN. Statins and outcomes in patients with bloodstream infection: a propensity-matched analysis. Crit Care Med. 2012;40(4):1064-1071. [CrossRef] [PubMed]
 
Egan A, Colman E. Weighing the benefits of high-dose simvastatin against the risk of myopathy. N Engl J Med. 2011;365(4):285-287. [CrossRef] [PubMed]
 
Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol. 2012;56(2):374-380. [CrossRef] [PubMed]
 
Link E, Parish S, Armitage J, et al; SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008;359(8):789-799. [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]
 
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]
 
Heeschen C, Hamm CW, Laufs U, Böhm M, Snapinn S, White HD. Withdrawal of statins in patients with acute coronary syndromes. Circulation. 2003;107(3):e27. [CrossRef] [PubMed]
 
McGowan MP; Treating to New Target (TNT) Study Group. There is no evidence for an increase in acute coronary syndromes after short-term abrupt discontinuation of statins in stable cardiac patients. Circulation. 2004;110(16):2333-2335. [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]
 
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