these only reached statistical significance on 1 study day (day 7 for AST and day 9 for ALT), and it is debatable whether they were of any clinical significance.3
Rebuttal From Drs Mermis and Simpson
Caution is noted when observing the small decrease in days free of renal or hepatic failure in the rosuvastatin group, an effect that may be present because of the number of secondary outcomes analyzed. Care must be taken to avoid generalizing results from only one of many trials to guide decisions regarding patient care. Although the rosuvastatin study did not suggest a benefit in the subgroup of patients prescribed statins before the development of ARDS, this subgroup was defined post hoc as patients on statins prior to the development of ARDS who had not received their statin for ⱖ 48 h.3 Many statins have short half-lives, and even for the statins with longer half-lives, three or more half-lives may have passed, and as such, the intervention may have more closely resembled reinitiation of a previous therapy rather than continuing therapy with therapeutic levels.
Joel D. Mermis, MD; Steven Q. Simpson, MD, FCCP;
We agree with Drs Mermis and Simpson on a number of points. Statin use in critically ill patients is not as simple as continuing the patient’s outpatient medication. These medications may have real interactions with commonly used medications in the ICU, and dose adjustments may be warranted in specific clinical scenarios. Any use must include careful monitoring for possible adverse effects. Given the widespread use of statins in the general community, critical care clinicians will continue to face the decision about continuing statin therapy on an almost daily basis. With careful monitoring for potential adverse effects, judicious continued statin therapy is appropriate while we await more definitive evidence. We remain of the opinion that the potential benefits of continued statin therapy in the ICU outweigh the risks. Any future randomized trials of continuing or discontinuing a patient’s prescribed statin upon ICU admission should involve well-defined safety monitoring, including studies of muscle strength and function.
References 1. Mermis JD, Simpson SQ. Counterpoint: should patients receiving statins prior to ICU admission be continued on statin therapy? No. Chest. 2014;146(6):1433-1435. 2. Flannery AH, Kruger PS. Point: should patients receiving statins prior to ICU admission be continued on statin therapy? Yes. Chest. 2014;146(6):1431-1433. 3. 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.
1436 Point and Counterpoint
Kansas City, KS
We agree that the pleotropic effects of statins provide mechanistic plausibility for treating critically ill patients. However, over the past decades, we have been baited with mechanistically promising antiinflammatory and other treatments, such as anti-tumor necrosis factor therapies, IL-1ra, and drotrecogin a, which have all failed to benefit patients. We are, sadly, left without specific therapies for common critical illnesses, such as sepsis or ARDS. Understandably, we are eager for new therapies. Drs Flannery and Kruger1 point out that discontinuing a patient’s statin medication at ICU admission could result in inadvertently not resuming the medication at ICU or hospital discharge. In the modern era of electronic medical records and pharmacist-driven medicine reconciliation, data demonstrate that this is less of a concern.2 Therefore, the decision really concerns the risk-benefit of continuing the medication during a patient’s critical illness. Our opponents cite multiple studies that provide support for continuation of statins in several critical illnesses, including candidemia, sepsis, ventilator-associated pneumonia, and delirium. We believe that their conclusions overstate the current evidence. Nearly all these studies supporting statin continuation evaluated a small population and were observational in nature. Observational studies evaluating potential benefits of statin use across a broad range of indications have been contradictory in their results and risk healthy user bias. Such reports have suggested that statins reduce the risk of a broad range of diseases, including infection, fractures, VTE, and other illnesses, but a large study
AFFILIATIONS:
From the Division of Pulmonary and Critical Care Medicine, University of Kansas School of Medicine. 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. 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: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-2226
[
146#6 CHEST DECEMBER 2014
]
of . 129,000 patients taking statins found that all these reported benefits were attributable to selection bias and confounding.3 Similarly, the promise for statin use in critically ill patients provided by observational studies has been dispelled by more rigorous studies that closely examined for healthy user bias. For example, one nested cohort study and one observational study suggested that statin continuation provided mortality benefit.4,5 However, a study in 1,895 patients on statins examining for healthy user bias in the 354 patients in whom statins were continued following admission for pneumonia and sepsis found the mortality benefit no longer evident after propensity scoring accounted for the impact of healthy user bias.6 Although a few reports suggested that statins provide protection against ICU delirium, these studies are again observational. For now, we feel compelled to rely on high-level evidence, specifically randomized controlled trials. In one randomized trial, prior statin users continued on statins in the ICU demonstrated a 28-day mortality reduction, which is of questionable benefit because the same cohort of patients did not experience reduced Sequential Organ Failure Assessment scores, hospital lengths of stay, or 90-day mortality. Although the benefit of statin continuation in critically ill patients is not proven, the two largest randomized trials evaluating statins in critically ill patients demonstrate hazard. The Rosuvastatin in Sepsis-Induced Acute Respiratory Distress Syndrome trial demonstrated increased risk of renal and hepatic dysfunction, and the
journal.publications.chestnet.org
Statins and Ventilator-Associated Pneumonia study was stopped for futility after simvastatin demonstrated a 6% absolute increase in 28-day mortality.7,8 High-level evidence of benefit from statin continuation is lacking, whereas safety concerns remain. We recommend discontinuing statins on ICU admission in critically ill patients.
References 1. Flannery AH, Kruger PS. Point: should patients receiving statins prior to ICU admission be continued on statin therapy? Yes. Chest. 2014;146(6):1431-1433. 2. Conklin JR, Togami JC, Burnett A, Dodd MA, Ray GM. Care transitions service: a pharmacy-driven program for medication reconciliation through the continuum of care. Am J Health Syst Pharm. 2014;71(10):802-810. 3. Smeeth L, Douglas I, Hall AJ, Hubbard R, Evans S. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol. 2009;67(1): 99-109. 4. 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. 5. 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. 6. Yende S, Milbrandt EB, Kellum JA, et al. Understanding the potential role of statins in pneumonia and sepsis. Crit Care Med. 2011;39(8): 1871-1878. 7. 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. 8. Papazian L, Roch A, Charles PE, et al; STATIN-VAP Study Group. Effect of statin therapy on mortality in patients with ventilatorassociated pneumonia: a randomized clinical trial. JAMA. 2013;310(16):1692-1700.
1437
Rebuttal From Drs Mermis and Simpson
Caution is noted when observing the small decrease in days free of renal or hepatic failure in the rosuvastatin group, an effect that may be present because of the number of secondary outcomes analyzed. Care must be taken to avoid generalizing results from only one of many trials to guide decisions regarding patient care. Although the rosuvastatin study did not suggest a benefit in the subgroup of patients prescribed statins before the development of ARDS, this subgroup was defined post hoc as patients on statins prior to the development of ARDS who had not received their statin for ⱖ 48 h.3 Many statins have short half-lives, and even for the statins with longer half-lives, three or more half-lives may have passed, and as such, the intervention may have more closely resembled reinitiation of a previous therapy rather than continuing therapy with therapeutic levels.
Joel D. Mermis, MD; Steven Q. Simpson, MD, FCCP;
We agree with Drs Mermis and Simpson on a number of points. Statin use in critically ill patients is not as simple as continuing the patient’s outpatient medication. These medications may have real interactions with commonly used medications in the ICU, and dose adjustments may be warranted in specific clinical scenarios. Any use must include careful monitoring for possible adverse effects. Given the widespread use of statins in the general community, critical care clinicians will continue to face the decision about continuing statin therapy on an almost daily basis. With careful monitoring for potential adverse effects, judicious continued statin therapy is appropriate while we await more definitive evidence. We remain of the opinion that the potential benefits of continued statin therapy in the ICU outweigh the risks. Any future randomized trials of continuing or discontinuing a patient’s prescribed statin upon ICU admission should involve well-defined safety monitoring, including studies of muscle strength and function.
References 1. Mermis JD, Simpson SQ. Counterpoint: should patients receiving statins prior to ICU admission be continued on statin therapy? No. Chest. 2014;146(6):1433-1435. 2. Flannery AH, Kruger PS. Point: should patients receiving statins prior to ICU admission be continued on statin therapy? Yes. Chest. 2014;146(6):1431-1433. 3. 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.
1436 Point and Counterpoint
Kansas City, KS
We agree that the pleotropic effects of statins provide mechanistic plausibility for treating critically ill patients. However, over the past decades, we have been baited with mechanistically promising antiinflammatory and other treatments, such as anti-tumor necrosis factor therapies, IL-1ra, and drotrecogin a, which have all failed to benefit patients. We are, sadly, left without specific therapies for common critical illnesses, such as sepsis or ARDS. Understandably, we are eager for new therapies. Drs Flannery and Kruger1 point out that discontinuing a patient’s statin medication at ICU admission could result in inadvertently not resuming the medication at ICU or hospital discharge. In the modern era of electronic medical records and pharmacist-driven medicine reconciliation, data demonstrate that this is less of a concern.2 Therefore, the decision really concerns the risk-benefit of continuing the medication during a patient’s critical illness. Our opponents cite multiple studies that provide support for continuation of statins in several critical illnesses, including candidemia, sepsis, ventilator-associated pneumonia, and delirium. We believe that their conclusions overstate the current evidence. Nearly all these studies supporting statin continuation evaluated a small population and were observational in nature. Observational studies evaluating potential benefits of statin use across a broad range of indications have been contradictory in their results and risk healthy user bias. Such reports have suggested that statins reduce the risk of a broad range of diseases, including infection, fractures, VTE, and other illnesses, but a large study
AFFILIATIONS:
From the Division of Pulmonary and Critical Care Medicine, University of Kansas School of Medicine. 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. 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: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-2226
[
146#6 CHEST DECEMBER 2014
]
of . 129,000 patients taking statins found that all these reported benefits were attributable to selection bias and confounding.3 Similarly, the promise for statin use in critically ill patients provided by observational studies has been dispelled by more rigorous studies that closely examined for healthy user bias. For example, one nested cohort study and one observational study suggested that statin continuation provided mortality benefit.4,5 However, a study in 1,895 patients on statins examining for healthy user bias in the 354 patients in whom statins were continued following admission for pneumonia and sepsis found the mortality benefit no longer evident after propensity scoring accounted for the impact of healthy user bias.6 Although a few reports suggested that statins provide protection against ICU delirium, these studies are again observational. For now, we feel compelled to rely on high-level evidence, specifically randomized controlled trials. In one randomized trial, prior statin users continued on statins in the ICU demonstrated a 28-day mortality reduction, which is of questionable benefit because the same cohort of patients did not experience reduced Sequential Organ Failure Assessment scores, hospital lengths of stay, or 90-day mortality. Although the benefit of statin continuation in critically ill patients is not proven, the two largest randomized trials evaluating statins in critically ill patients demonstrate hazard. The Rosuvastatin in Sepsis-Induced Acute Respiratory Distress Syndrome trial demonstrated increased risk of renal and hepatic dysfunction, and the
journal.publications.chestnet.org
Statins and Ventilator-Associated Pneumonia study was stopped for futility after simvastatin demonstrated a 6% absolute increase in 28-day mortality.7,8 High-level evidence of benefit from statin continuation is lacking, whereas safety concerns remain. We recommend discontinuing statins on ICU admission in critically ill patients.
References 1. Flannery AH, Kruger PS. Point: should patients receiving statins prior to ICU admission be continued on statin therapy? Yes. Chest. 2014;146(6):1431-1433. 2. Conklin JR, Togami JC, Burnett A, Dodd MA, Ray GM. Care transitions service: a pharmacy-driven program for medication reconciliation through the continuum of care. Am J Health Syst Pharm. 2014;71(10):802-810. 3. Smeeth L, Douglas I, Hall AJ, Hubbard R, Evans S. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol. 2009;67(1): 99-109. 4. 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. 5. 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. 6. Yende S, Milbrandt EB, Kellum JA, et al. Understanding the potential role of statins in pneumonia and sepsis. Crit Care Med. 2011;39(8): 1871-1878. 7. 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. 8. Papazian L, Roch A, Charles PE, et al; STATIN-VAP Study Group. Effect of statin therapy on mortality in patients with ventilatorassociated pneumonia: a randomized clinical trial. JAMA. 2013;310(16):1692-1700.
1437
