key: cord-0993850-yiqwhy4u
authors: Andrews, Laura; Goldin, Laurel; Shen, Yan; Korwek, Kimberly; Kleja, Kacie; Poland, Russell E.; Guy, Jeffrey; Sands, Kenneth E.; Perlin, Jonathan B.
title: Discontinuation of atorvastatin use in hospital is associated with increased risk of mortality in COVID‐19 patients
date: 2022-02-14
journal: J Hosp Med
DOI: 10.1002/jhm.12789
sha: 6627096521087506dc2fec535b7e227060432058
doc_id: 993850
cord_uid: yiqwhy4u

BACKGROUND: Statins are a commonly used class of drugs, and reports have suggested that their use may affect COVID‐19 disease severity and mortality risk. OBJECTIVE: The purpose of this analysis was to determine the effect of discontinuation of previous atorvastatin therapy in patients hospitalized for COVID‐19 on the risk of mortality and ventilation. METHODS: Data from 146,413 hospitalized COVID‐19 patients were classified according to statin therapy. Home + in hospital atorvastatin use (continuation of therapy); home + no in hospital atorvastatin use (discontinuation of therapy); no home + no in hospital atorvastatin use (no statins). Logistic regression was performed to assess the association between atorvastatin administration and either mortality or use of mechanical ventilation during the encounter. RESULTS: Continuous use of atorvastatin (home and in hospital) was associated with a 35% reduction in the odds of mortality compared to patients who received atorvastatin at home but not in hospital (odds ratio [OR]: 0.65, 95% confidence interval [CI]: 0.59–0.72, p < .001). Similarly, the odds of ventilation were lower with continuous atorvastatin therapy (OR: 0.70, 95% CI: 0.64–0.77, p < .001). CONCLUSIONS: Discontinuation of previous atorvastatin therapy is associated with worse outcomes for COVID‐19 patients. Providers should consider maintaining existing statin therapy for patients with known or suspected previous use.

As the COVID-19 pandemic has progressed, various drugs have been proposed for repurposing as potential treatment candidates.

Candidates drawn from experience with other coronaviruses or mechanistic hypotheses have been tested for performance against COVID-19 primarily in observational studies, with reports indicating that hundreds of different medications have been administered to these patients in attempt to identify agents that can potentially reduce the severity of COVID-19 disease and modify patient outcomes. 1 Statins are among the most widely use class of drugs, and have been used since the late 1980s for their cholesterol-lowering effects and impact on the risk of coronary heart disease. These drugs are also known to have anti-inflammatory and immunomodulatory properties, and this has led to the repurposing of this drug for certain infectious diseases, including COVID-19.The anti-inflammatory effects of statins have been linked to possible decreases in influenza-related hospitalizations and deaths. 2 Alternatively, or additionally, statin treatment may improve vascular and endothelial function in patients with severe COVID-19 infection through upregulation of the ACE2 receptor. 3, 4 Observational studies have indicated a possible association between statin intake and a beneficial effect on COVID-19 clinical symptoms in susceptible populations. 5, 6 Observational studies have linked statin use to lower mortality among patients with COVID-19, however these studies highlighted possible variation in the effect based on statin dosage, patient characteristics, or COVID-19 disease severity. [7] [8] [9] Yet not all studies have shown these beneficial effects on mortality or disease severity. 10 There was a high degree of certainty regarding medications that were documented in these lists (i.e., medications that appear on the list reflect administrations), but these data on home medications can be incomplete for a variety of reasons. Thus, patients with hospital administration of statins but no documented home use may represent a mixed population of new users and current users and therefore this population was excluded in the current analysis. Duration of outpatient medication use is not captured at admission and therefore unavailable for this analysis.

Logistic regression was performed to assess the association between atorvastatin administration and either mortality or use of mechanical The recently completed CORONADO study found that routine statin use was associated with increased morality in hospitalized COVID-19 patients with type 2 diabetes mellitus. 16 In contrast, another retrospective cohort study found that while inpatient statin use was associated reduced mortality, especially among those with a history of diabetes mellitus. 17 analysis were similar between the groups, suggesting that the use of statins was likely not a major factor in treatment decision-making.

Additional controlled studies will be needed to further understand the risk of discontinuation of statin therapy in hospitalized COVID-19

patients and the potential benefit to beginning therapy in those who are statin-naïve.

The association of the discontinuation of statins with the risk of worse outcomes is not unprecedented. Perioperative exposure to atorvastatin has been associated with a reduction in the risk of mortality and certain complications. [19] [20] [21] Furthermore, patients who stopped statin therapy after a myocardial infarction had a higher risk of mortality than patients who never used statins. 22 Recommendations from the American College of Cardiology/American Heart Association favor the continuation of statin therapy for patients undergoing surgery to reduce the risk of cardiac complications. 23 As there is an increased occurrence of cardiovascular events in COVID-19 patients, continuous stain therapy may be providing protective effects through pleiotropic benefits on inflammation, oxidative stress, coagulation, and endothelial function. 24 In our data set, we attempted to identify those patients whose in-hospital administration of atorvastatin was a continuation of their ongoing use of this medication for other conditions. Due to the nature of our data, we were limited to medication lists reported by the patient or their representative at admission. Such lists are known to often be incomplete or not supplied for a variety of reasons, such as communication challenges or patient condition at admission, and thus these results should be interpreted with caution. We excluded patients with in hospital atorvastatin administration but no previous in-home use as we could not distinguish between de novo atorvastatin administration or a lack of documentation of home medication in these patients. In contrast, those who had indicated home use of atorvastatin but had no in-hospital use are highly likely to represent a discontinuation of previous therapy, as medication administration data in our system have been independently verified for both research and billing purposes.

Our data set reflects the overall population in that those patients who had statin administration were older on average than those patients with no known statin exposure. Although this variable was taken into account as part of the regression, the younger age of the no-statin group would favor reduced mortality, as age has been consistently identified as a risk factor for COVID-19 mortality. The observation that statin use was associated with reduced mortality compared to no-statin use could argue that our finding might have been even greater if the ages of these two groups was comparable.

Other limitations of this analysis are those common to studies using retrospective data, namely a lack of control of confounding variables and the inability to interpret a relationship beyond correlation. We simplified our analysis to atorvastatin-only in order to control for any potential differences between individual medications; additional work is underway to confirm these findings for other commonly used statins. We also did not investigate how atorvastatin dose, timing, or days of therapy could affect mortality risk as these were beyond the scope of the current analysis; additional work on these questions is also underway.

Additional limitations are related to the nature of the data source itself. While the HCA enterprise data warehouse is powerful, it is limited in the fact that it receives data streams from >185 facilities, nearly all of which developed their EHR systems independently. A decade of effort to standardize/normalize data has allowed for much to be gained from this data source. However, local variation in data-related processes is a known issue and there are still a few areas that are not yet at the quality needed for research, such as laboratory results, and thus unavailable for analysis in this way.

In total, our analysis supports the continuation of statin therapy for COVID-19 patients. Providers should consider maintaining existing statin therapy for patients with known or suspected previous use. Additional study will be needed to elucidate the potential benefit of statin treatment among COVID-19 patients with no history of previous use.

This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors would like to acknowledge Charity Loput,

PharmD.

The authors declare that there are no conflicts of interest.

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http://orcid.org/0000-0001-8981-3304Kimberly Korwek http://orcid.org/0000-0001-8687-8487