key: cord-0839270-3dxk95ha
authors: Li, Weijia; Rios, Saul; Nagraj, Sanjana; Hajra, Adrija; Saralidze, Tinatin; Varrias, Dimitrios; Mathai, Sheetal Vasundara; Novakovic, Marko; Hupart, Kenneth H.; Miles, Jeremy A.; Katamreddy, Adarsh; Palaiodimos, Leonidas; Faillace, Robert T.
title: Statin use in hospitalized patients with COVID-19: A comprehensive analysis of the New York City Public Hospital System
date: 2022-03-14
journal: Am J Med
DOI: 10.1016/j.amjmed.2022.02.018
sha: cb08a9d9f37bd49654354dac362f8ae5847824c1
doc_id: 839270
cord_uid: 3dxk95ha

INTRODUCTION: Statins have been commonly used for primary and secondary cardiovascular prevention. We hypothesized that statins may improve in-hospital outcomes for hospitalized patients with COVID-19 due to its known anti-inflammatory effects. METHODS: We conducted a retrospective study at the largest municipal healthcare system in the United States including adult patients who were hospitalized for COVID-19 between 03/01/2020 and 12/01/2020. The primary endpoint was in-hospital death. Propensity score matching was conducted to balance possible confounding variables between patients receiving statins during hospitalization (statin group) and those not receiving statins (non-statin group). Multivariate logistic regression was used to evaluate the association of statin use and other variables with in-hospital outcomes. RESULTS: 8897 patients were eligible for study enrollment with 3359 patients in the statin group and 5538 patients in the non-statin group. After propensity score matching, both the statin and non-statin groups included 2817 patients. Multivariate logistic regression analysis showed that the statin group had a significantly lower risk of in-hospital mortality (OR 0.71; (0.63, 0.80); P<0.001) and mechanical ventilation (OR 0.80; (0.71, 0.90); p<0.001) compared to the non-statin group. CONCLUSION: Statin use was associated with lower likelihood of in-hospital mortality and invasive mechanical ventilation in hospitalized patients with COVID-19.

COVID-19 has placed a significant strain on healthcare systems around the world with more than 230 million cases and 4.5 million deaths to date. (1) . The United States and, particularly New York City, have been severely affected, particularly during the spring of 2020. (2, 3) The causal agent for COVID-19, SARS-CoV-2 invades the host's cells via the angiotensin- In prior studies, the use of statins has been proven to reduce mortality in patients with seasonal influenza and was proposed as a treatment for the Middle Eastern Respiratory Syndrome (MERS) infection. (9, 10) As such, our study aims to evaluate whether statin use is associated with improved in-hospital outcomes in hospitalized patients with moderate-to-severe COVID-19.

We conducted a retrospective observational cohort study at New York City Health + Hospitals (NYC H+H), the largest municipal healthcare system in the United States serving more than one million residents within the New York City metropolitan area. We included adult patients who tested positive for SARS-CoV-2 via polymerase chain reaction assays of nasopharyngeal specimens and who were hospitalized in one of the eleven acute care hospitals within the NYC H+H system during the study period (03/01/2020 through 12/01/2020).

All patients were classified into two groups: The statin group and the non-statin group. The statin group included patients who received at least one of the FDA-approved statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) during their hospitalizations. The non-statin group included those patients who did not receive any statins during their hospitalizations. Patients were excluded if they remained hospitalized at the end of the study period or there was missing information regarding body mass index.

Baseline characteristics including age, gender, history of hypertension, diabetes mellitus, obesity, coronary artery disease, heart failure, atrial fibrillation, stroke/transient ischemic attack (TIA), pulmonary hypertension, chronic obstructive pulmonary disease, and asthma were collected.

Medications that were commonly used in patients with COVID-19 or were proposed as possibly having a therapeutic effect on COVID-19 by prior studies (hydroxychloroquine(11), remdesivir (12) , glucocorticoid (13) , ceftriaxone (14) , azithromycin (14) , piperacillintazobactam (15) , vancomycin (15) , cefepime (15) , angiotensin converting enzyme inhibitors (ACEi) (16) , angiotensin receptor blockers (ARB) (16) , angiotensin receptor-neprilysin inhibitor (ARNi) (16) , tocilizumab(17)) were also collected as possible confounding variables. Patients were selected based on eligibility criteria and patient data were retrieved from our electronic medical record system.

The study was approved by the Biomedical Research Alliance of New York (BRANY) Institutional Review Board (IRB number 20-12-228-373). Informed consent was waived based on the retrospective nature of our study carrying minimal risks to the study population.

The primary outcome of the study was in-hospital mortality. The secondary outcomes included intensive care unit (ICU) admission and need for invasive mechanical ventilation. Continuous variables were described as mean ± standard deviation. Categorical variables were reported as absolute numbers and percentages. The standardized mean difference (SMD) was calculated to assess the difference between the two groups. Propensity score matching using nearest neighbor matching with a caliper of 0.1 standard deviations of the logit of the propensity scores was conducted to improve the comparability between the two groups. The baseline characteristics were incorporated into the propensity score matching model. (hydroxychloroquine, remdesivir, glucocorticoid, tocilizumab) that were proposed to affect inhospital outcomes of COVID-19. One-to-one ratio matching was adopted based on sample size.

An SMD less than 0.1 is considered well-matched between the two groups. Univariate logistic regression was performed individually for each study outcome: in-hospital mortality, ICU admission, and mechanical ventilation. Those variables with p value less than 0.1 in the univariate analyses were incorporated into the multivariate logistic regression model. The threshold of statistical significance was p<0.05. All analyses were conducted using R 3.6.3 version (RStudio software, RStudio, Inc.).

A total of 8897 patients were eligible for study enrollment after excluding 160 patients who had not been discharged at the end of the study period, 60 patients who were not admitted to our acute care hospitals, and 1682 that did not have available BMI. 3359 patients were found to be in the statin group and 5538 patients were in the non-statin group. After propensity score matching, both the statin and non-statin groups contained 2817 patients with mean age around 67 years, 67% of whom were male. Hypertension, obesity, and diabetes mellitus were the three most common comorbidities. The matched cohorts were balanced for age, gender, comorbidities including hypertension, diabetes, obesity, coronary artery disease, heart failure, atrial fibrillation, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, stroke/transient ischemic attack, prescriptions of other medications with SMD less than 0.10. (Table 1) We noticed that the univariate and multivariate logistic regression analysis suggested that hypertension was a protective factor against in-hospital mortality, but a significant interaction between hypertension and ACEi/ARB/ARNi use (p = 0.03) existed. After adding the interaction variables of hypertension and ACEi/ARB/ARNi use in the multivariate logistic regression model, hypertension was no longer a significant protective factor (p = 0.10). While, ACEi/ARB/ARNi use was statistically significantly associated with reduced in-hospital mortality [OR 0.41; (0.34, 0.50); P<0.001], suggesting the effect of hypertension was largely attributed to ACEi/ARB/ARNi use. (Table 2) 

Regarding admission to ICU, 21.1% (594 of 2817) patients in the statin group required admission to ICU compared to 22.8% (642 of 2817) patients in the non-statin group. Multivariate logistic regression analysis showed that the statin group had a trend towards a lower likelihood for ICU admission, although this association did not reach the threshold of statistical significance [OR 0.90; (0.79, 1.02); p=0.092]. Additionally, for the statin group patients increasing age was associated with reduced ICU admission. (Table 3) are also significant predictors of higher risk of requiring mechanical ventilation. Despite that heart failure appears to be a significant protective factor for mechanical ventilation, a possible interaction between statin use and heart failure exists (p = 0.23). After introducing the interaction variable of statin use and heart failure, the effect of heart failure was no longer significant (p = 0.40). (Table 4) 

We performed subgroup analyses using the outcome of ICU admission and mechanical ventilation as surrogates for COVID-19 severity, and the results showed that the statin group is 

We reassessed the effect of statin use on in-hospital mortality from 05/16/2020 to 12/01/2020 after the surge period in New York City (31) . After applying propensity score matching ( 

Our study found that the use of statins was independently associated with a significantly lower risk of in-hospital mortality and mechanical ventilation in patients hospitalized with COVID-19.

COVID-19 can generate an accentuated immune response which activates a systemic inflammatory cascade, often termed "cytokine storm" (32, 33) . Interaction of the SARS-CoV-2 with the host immune system results in inhibition of lymphopoiesis and accelerated lymphocyte apoptosis. (34) In later stages of the infection, continued virus replication disrupts host endothelial-epithelial barrier precipitating the release of inflammatory cytokines and infiltration of monocytes and neutrophils (32, 35) End-organ damage pathognomonic of COVID-19 associated inflammation occurs in the manifestation of acute respiratory distress syndrome with associated alveolitis and endothelial inflammation. (35) . Levels of inflammatory markers including C-reactive protein, interleukin-6, procalcitonin, ferritin, erythrocyte sedimentation rate, and serum amyloid A have been found strongly associated with the severity of COVID-19

whereas survivors from COVID-19 had significantly lower levels of IL-6 (36, 37) . Activation of the immune system and the subsequent inflammation are fundamental to the pathophysiology of COVID-19. Therefore, they form the basis of currently available treatment target options and monitors of disease progression (36, 37) .

Anti-inflammatory agents such as dexamethasone, tocilizumab, baricitinib are proven efficacious treatments for selected patients with severe COVID-19 (12, 13, 38, 39) . Given that the proven benefit of these agents is attributed to their anti-inflammatory properties, the association of statins with lower in-hospital mortality identified by our study suggests that this can also be attributed to their anti-inflammatory effects.

The anti-inflammatory effects of statins have been well-studied and reported independent of their cholesterol-lowering effects. In vitro studies have uniformly found statins to reduce the expression of cellular adhesion molecules thereby inhibiting leukocyte adhesion to endothelial cells (40, 41) . Specifically, they have been found to lower the expression of the integrin dimer CD11b and monocyte chemotactic protein-1on monocytes, and selectively inhibit leukocyte function antigen-1 (LFA-1) (8, 40) . By binding to a novel regulatory site within the β 2 integrin, statins inhibit LFA-1 and adhesion of lymphocytes to endothelial cells (40, 42) . This selective inhibition results in termination of the inflammatory cascade at a preliminary stage.

Clinical studies have corroborated these findings; the use of high dose atorvastatin was associated with a significant reduction in the levels of c-reactive protein, interleukin-1, interleukin-6, tumor necrosis factor and adhesions molecules (43) . Another HMG-CoA-reductase inhibitor, simvastatin showed a similar significant reduction in c-reactive protein and interleukin-6 levels(44). The PRINCE study validated these findings by demonstrating that pravastatin significantly reduced c-reactive protein levels independent of changes in lipid levels and may have distinctive anti-inflammatory effects. (45) The JUPITER study showed similar findings; the use of rosuvastatin significantly reduced c-reactive protein levels and cardiovascular events. (46) Although preliminary results from randomized controlled trials studying the role of statins in ARDS did not find a significant improvement in outcomes (47, 48) , on secondary analysis, statins demonstrated a mortality benefit when used within 48 hours of development of acute respiratory distress syndrome in patients with the hyperinflammatory sub-phenotype (47, 49) . Moreover, the anti-inflammatory property of statins has been applied in the treatment of non-cardiovascular diseases such as multiple sclerosis and rheumatoid arthritis. (50, 51) Statins showed modest, albeit clinically apparent anti-inflammatory effects in high-grade rheumatoid arthritis. These effects are postulated secondary to suppression of Th1-related immune responses and TNF-alpha in the synovial membranes (52) . Evidence from meta-analysis also suggests that statins may have a role in reducing cancer-related mortality and reducing exacerbations in patients with chronic obstructive pulmonary disease. (53) There have been studies evaluating the use of statins in COVID-19 patients. However, they differ from our study in remarkable ways. Saeed et al. in their retrospective observational study of COVID-19 patients found statins to be associated with a lower hospital mortality selectively in patients with diabetes mellitus.(54) They concluded that there was no difference in hospital mortality based on statin use in patients without history of diabetes. In our study, statins continued to demonstrate an association with significantly lower hospital mortality regardless of diabetes status. Our cohorts were balanced not only for diabetes, but also hypertension, obesity, coronary artery disease, heart failure, and atrial fibrillation among others with a larger sample and an analysis that employed propensity score matching and multivariate logistic regression.

Also, their single-center study was conducted during the initial COVID-19 surge when treatment protocols were in flux and underwent rapid changes, making study groups heterogeneous. Our study evaluated the role of statins, both during the initial surge period in NYC and after it, patients admitted to the ICU(55). The investigators did not find atorvastatin to improve outcomes in these patients. It is important to note that the study excluded patients who were routinely taking statins prior to hospitalization and tested only the 20 mg dosage form of atorvastatin.

Statin use could have influenced disease progression in the early stages of infection prior to hospitalization. We included all of the most common forms of statin therapy as well as patients irrespective of statin use prior to hospitalization. In addition, our findings suggested that the use of Renin-Angiotensin-Aldosterone System (RAAS) inhibitors were associated with significantly reduced in-hospital mortality in addition to the effect of statin therapy. Increasing age was found associated with a lower rate of ICU admission in our patient population, suggesting that age was likely incorporated into selection criteria for ICU admission in patients with COVID-19 infection especially during patient the surge period. Haas et.al. mentioned in their article that age could be considered to forgo ICU treatment in times of scarcity to prioritize younger patients. (56) Overall, statin use in such a largely diverse population derived from the largest municipal hospital system in the nation was found to be associated with lower in-hospital mortality regardless of disease severity. However, further investigation with randomized trials evaluating for dose-dependent effects of statins on COVID-19 outcomes, and effect of different agents within the same class of drugs are needed. The effect of routine use of statins on the early stages of COVID-19 infection also needs to be assessed.

The strengths of our study include a large study population from multiple hospitals across New York City, an epicenter of the COVID-19 pandemic. We used a strict methodology using propensity score matching and multivariate logistic regression to control for possible confounding factors. We did not restrict our analysis to a pre-defined and limited in-hospital length of stay allowing for accurate capturing of endpoints. Our study also evaluated the pandemic during two different phases, the surge and the period following it. To achieve this, we used a robust analysis incorporating subgroup analyses and sensitivity analyses of patients in the post-COVID-19 surge period.

We recognize that our study has important limitations. Although, propensity matched analysis was performed, being a retrospective study conducted from electronic medical records, the possibility of unmeasured confounders exists. An important bias to consider in retrospective studies is the "Healthy user effect"., It has been demonstrated that patients who adhere to statin use tend to be younger, engage in healthier lifestyles and see their primary care physician more often (57, 58) .

In addition, errors in medication reconciliation and documentation are possible, especially amidst soaring hospital admissions during the pandemic. Also, the duration of treatment with statins and medication noncompliance prior to hospitalization were not accounted for in the analysis and these carry the potential to affect outcomes. Another limitation is the possible significant different criteria for ICU admission across all of our different facilities. These also vary based on provider assessment, ICU bed capacity and available hospital resources.

In this multi-center study from the largest municipal healthcare system in the United States, located in the epicenter of the COVID-19 pandemic, statin use was associated with a lower risk of in-hospital mortality and mechanical ventilation for hospitalized COVID-19 patients.

The use of statins was independently associated with a significantly lower risk of in-hospital mortality and mechanical ventilation in patients hospitalized with COVID-19 infection in our hospital system. Statin use still had a significant association with reduced in-hospital mortality and mechanical ventilation after the COVID-19 patient surge period. In patients admitted to the intensive care unit, statin use was also associated with a lower of inhospital mortality. 

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