Rebuttal From Drs Mermis and Simpson

Abstract

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 α, 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 Kruger1Flannery AH Kruger PS Point: should patients receiving statins prior to ICU admission be continued on statin therapy? Yes.Chest. 2014; 146: 1431-1433Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar 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.2Conklin 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: 802-810Crossref PubMed Scopus (17) Google Scholar 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 of > 129,000 patients taking statins found that all these reported benefits were attributable to selection bias and confounding.3Smeeth 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: 99-109Crossref PubMed Scopus (188) Google Scholar 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.4Al 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: 12Crossref PubMed Scopus (35) Google Scholar, 5Bruyere 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: R83Crossref PubMed Scopus (22) Google Scholar 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.6Yende S Milbrandt EB Kellum JA et al.Understanding the potential role of statins in pneumonia and sepsis.Crit Care Med. 2011; 39: 1871-1878Crossref PubMed Scopus (98) Google Scholar 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 Statins and Ventilator-Associated Pneumonia study was stopped for futility after simvastatin demonstrated a 6% absolute increase in 28-day mortality.7Truwit 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: 2191-2200Crossref PubMed Scopus (371) Google Scholar, 8Papazian 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: 1692-1700Crossref PubMed Scopus (150) Google Scholar 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.