key: cord-1052647-3m8irg1a
authors: Mozaffari, Essy; Chandak, Aastha; Zhang, Zhiji; Liang, Shuting; Gayle, Julie; Thrun, Mark; Gottlieb, Robert L; Kuritzkes, Daniel R; Sax, Paul E; Wohl, David A; Casciano, Roman; Hodgkins, Paul; Haubrich, Richard
title: Clinical management of hospitalized COVID-19 patients in the United States
date: 2021-09-28
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab498
sha: cea4dcd396ccb4d8bc48bb4a5d410b2525be3d10
doc_id: 1052647
cord_uid: 3m8irg1a

OBJECTIVE: The objective of this study was to characterize hospitalized COVID-19 patients and describe their real-world treatment patterns and outcomes over time. METHODS: Adult patients hospitalized 5/1/2020–12/31/2020 with a discharge diagnosis of COVID-19 were identified from the Premier Healthcare Database. Patient and hospital characteristics, treatments, baseline severity based on oxygen support, length of stay (LOS), ICU utilization and mortality were examined. RESULTS: The study included 295 657 patients (847 hospitals), with median age(IQR) of 66(54-77) years. Majority were male, white, and over 65. Approximately 85% had no supplemental oxygen charges (NSOc) or low-flow oxygen (LFO) at baseline, while 75% received no more than NSOc or LFO as maximal oxygen support at any time during hospitalization. Remdesivir (RDV) and corticosteroid treatment utilization increased over time. By December, 50% were receiving RDV and 80% were receiving corticosteroids. A higher proportion initiated COVID-19 treatments within two days of hospitalization in December vs May (RDV: 87% vs 40%; corticosteroids: 93% vs 62%; convalescent plasma: 68% vs 26%). There was a shift toward initiating RDV in patients on NSOc or LFO (68.0% (May) vs. 83.1% (December)). Median LOS decreased over time. Overall mortality was 13.5% and it was highest for severe patients (invasive mechanical ventilation/ECMO (IMV/ECMO):53.7%, high-flow oxygen/non-invasive ventilation (HFO/NIV):32.2%, LFO:11.7%, NSOc:7.3%). ICU use decreased, while mortality decreased for NSOc and LFO. CONCLUSIONS: Clinical management of COVID-19 is rapidly evolving. This large observational study found that use of evidence-based treatments increased from May to December 2020, while improvement in outcomes occurred over this time-period.

In the United States (US), there was a 25% reduction in COVID-19 mortality rates from January to April 2020 and a substantial decline in risk-adjusted mortality rates between March and August 2020. Despite initial improvements in mortality, studies in the US have observed considerable variation in COVID-19 outcomes by hospital and geographic region. Higher community case rates of COVID-19 were associated with worse outcomes by hospital, accounting for some of this variation.

Regional differences in clinical management of COVID-19 may also explain some of the variation in outcome, but data are limited and have mostly been single center studies or focused on small sample sizes. Additionally, few of these studies describe the impact of disease severity on mortality and outcomes in patients with COVID-19 in real-world settings. Studies that account for more recent temporal changes in COVID-19 management are also limited since there is a lag in data availability in many data sources (e.g., insurance claims databases). Existing studies have focused on data through August 2020.

A c c e p t e d M a n u s c r i p t 6 We therefore conducted an analysis using one of the largest COVID-19 hospitalization datasets in the US with geographic representation across the country and included more recent data from May 2020 through end of December 2020. The objective of this study was to characterize hospitalized patients with a discharge diagnosis of COVID-19 and describe real-world treatment patterns and outcomes over time among hospitalized COVID-19 patients.

This study used the Premier Healthcare Database, an administrative all-payer database that covers approximately 20% of all US hospitalizations from 45 states and DC. The data includes diagnosis codes, procedure codes, admission month, discharge month, and costs per day relative to admission date. However, actual dates and time stamps are not available to ensure patient privacy. Hence, all baseline variables are examined within first two days of hospitalization.

Adult patients (≥18 years) hospitalized 5/1/20-12/31/20 with a primary or secondary discharge diagnosis of COVID-19 (ICD-10-CM Code: U07.1) were included. Only the first admission during the study period was included for each patient. The accuracy of ICD-10-CM code U07.1 has been previously validated; this code has been shown to be a reasonable measure for tracking inpatient COVID-19 discharges and associated costs.

Patients were excluded from the study if they were pregnant or had received RDV as part of a clinical trial/study (identified through RDV-related hospital charges that also mentioned "Study" or "Placebo"). Patients who had extended length of stay of >100 days and patients with incomprehensible/incomplete data on hospitalization were also excluded.

A c c e p t e d M a n u s c r i p t 7

Study variables included demographics and key baseline comorbidities occurring in more than 5% of patients. Comorbidities were derived from ICD-10-CM diagnosis codes of chronic conditions present as the admitting or discharge diagnoses. Discharge diagnoses of sepsis, pulmonary embolism, respiratory failure, pneumonia, and hypoxemia among other conditions were also examined. ICU utilization and ICU LOS over time were also evaluated. All-cause in-hospital mortality was identified from "expired" discharge status and examined over time.

Descriptive analyses were conducted; categorical variables were summarized by number of observations and percentage (%) and continuous variables were summarized using median and interquartile range (IQR). Demographics, hospital, and hospitalization characteristics were summarized for the overall COVID-19 cohort. Treatment utilization, LOS, ICU, and mortality outcomes were summarized by month of admission (May-December) and were stratified by baseline severity. LOS and ICU LOS outcomes were right skewed by patients who died during the hospitalization since both groups of patients were examined. Adjusted mortality rates by month and stratified by baseline ordinal scale were also extracted using a logistic regression model. The following variables were included in the adjusted model: age, gender, race, ethnicity, and comorbidities (cerebrovascular disease, COPD, CHF, diabetes mellitus, dementia, hypertension, myocardial infarction, obesity, and renal disease).

Given the de-identified and retrospective nature of the data obtained from the Premier Healthcare Database, as well as the observational study design, written patient consent was neither required nor sought.

A c c e p t e d M a n u s c r i p t 9

There were 295 657 patients in the study cohort from 847 hospitals (Supplementary Figure 1) , after applying the inclusion and exclusion criteria. Median age (IQR) was 66 (54-77) years; more than half were male, majority were white, over 65 years old with Medicare as primary payor ( Table 1,   Supplementary Table 1 ). Most patients in the sample were from non-teaching, urban hospitals in the South or Midwest and were admitted from a non-health care facility as an emergency admission (Supplementary Table 1 ).

For more than half of the patients, respiratory failure (62.1%) and pneumonia (77.0%) were recorded in the discharge diagnoses, while sepsis was reported for 25.6% of patients ( Table 1) . At baseline, ~85% patients and 74-76% patients received no more than NSOc or LFO as maximal oxygen support at any time during the hospitalization, which remained stable over the study period ( (Figure 2) . These findings were generally consistent across regions (data not shown).

Additionally, use of RDV and corticosteroid combination during the study period was 37.6%, corticosteroids and convalescent plasma combination was 15.8%, and RDV and convalescent plasma (Figure 4) . ICU use and mortality for all severity groups are also shown in Figure 4 . The mortality for IMV/ECMO group was 47% in May/June compared to 59% in November/December (Figure 4) . After adjusting for age, gender, race, ethnicity, and comorbidities (cerebrovascular disease, COPD, CHF, diabetes mellitus, dementia, hypertension, myocardial infarction, obesity, and renal disease), the mortality rate was 9% in May and 7% in December for patients on NSOc at baseline, 18% in May and 13% in December for patients on LFO at baseline, 39% in May and 36% in December for patients on HFO/NIV at baseline and 46%

in May and 60% in December for patients on IMV/ECMO at baseline (Supplementary Figure 3) . While there were general improvements in some outcomes and use of treatments over time, there were some notable exceptions. Overall mortality rates observed in our study showed a modest continual downward trend over time, but mortality by severity level showed that patients in the IMV/ECMO and HFO/NIV groups had a slight increase in mortality in recent months, while the NSOc A c c e p t e d M a n u s c r i p t 13 and LFO groups had slight decreases. These results remained consistent in the adjusted analyses. It is important to consider that because of the changing conditions of the pandemic, thresholds for hospital admission may have changed, and it is possible that less severely ill patients were being admitted in later time periods. More likely, however, is that more critically ill patients were treated earlier in the pandemic with mechanical ventilation, while later managed with prone positioning and other non-invasive strategies. This trend would shift the burden of disease among those in the IMV/ECMO group in particular to be of greater severity. In support of this practice change, use IMV/ECMO in the first two days of the hospital course declined from 7.9% in May to 4.2% in December 2020, and thus the patients that received mechanical ventilation reflected a more ill cohort over time.

Use of medical treatments with proven benefits in clinical trials increased. More recently, however, the proportions of use for RDV and corticosteroids appeared to have leveled somewhat. RDV use increased from 5.0% in May to 51.1% in October then remained at roughly 50% since then. Similarly, corticosteroid use increased from 34.3% in May to 79.2% in July, but utilization has leveled off at an average just slightly above 80%. Roughly 85% of the study population were in the two lowest severity categories that may experience the greatest benefit from RDV use, and the results of this study suggest that there remain opportunities to improve treatment for these patients.

To date, there have been few studies that examine the patient and hospital characteristics and clinical management of COVID-19 in a large sample of patients, and findings from these studies have

varied. An observational US cohort study from a large national health insurer (N=38 517 adults across 955 US hospitals) conducted from 1/1/2020-6/30/2020 found that hospitals in the Northeast, medium to large hospitals, and hospitals with high county-level COVID-19 case rates had worse risk-standardized event rates of 30-day in-hospital mortality or referral to hospice. hydroxychloroquine and other treatments but did not stratify by severity of disease. The largest study to date (N=192 550) described characteristics and outcomes over the first 6 months of the pandemic and found a significant decrease in mortality, but unlike did not describe outcomes by baseline severity.

Variation within and among these studies and compared with the present study may be due to the paucity of high-quality evidence to back clinical practice, differences in hospital resources to manage practices such as prone positioning, availability and access to medications such as RDV, as well as unmeasured differences across treatment centers. Additionally, the present study period of May to December eliminates the early period of the pandemic (included in all other studies) when mortality rates were highest. These studies along with the current study highlight the need for robust methodologies that account for key factors specific to the rapidly changing COVID-19 disease landscape when conducting comparative analyses of evolving COVID-19 treatments. Nonrandomized comparative effectiveness studies of COVID-19 treatments should consider potential determinants of treatment decisions such severity, calendar time, fever, low oxygen saturation, presence of comorbidities, and elevated inflammatory biomarkers.

A key strength of our study is that it describes the characteristics of hospitalized COVID-19 patients, along with comorbidities, treatment, severity, and outcomes, in a large, geographically diverse sample that covers about 20% of hospitalization in the US. Another strength of this study is that it provides a longer period (8 months) of characterization of COVID-19 hospitalizations than most published studies and illustrates how treatment patterns and outcomes changed over time. This study includes more recent data and excludes data from the early months of the pandemic in which high mortality was related to limited knowledge of disease and overwhelmed hospital capacity. In addition, this study also provides a more detailed picture of how outcomes changed over time in patients of different baseline severity levels, which can serve as important references for future A c c e p t e d M a n u s c r i p t 15 comparative research. Limitations include the potential for misclassification from using administrative data to define clinical variables; variables based on billing and ICD-10 coding may misclassify or underrepresent comorbid conditions, treatments, procedures, and therapies. Because not all hospitals consistently bill for oxygen supply or oxygen devices, particularly LFO, it is possible that the category of NSOc in our study included patients who received some level of oxygen that was not billed for, but it was included in the room charge. Thereby, in order to capture this limitation, we denote this group as NSOc.

Our study describes the demographics, hospital characteristics and treatments of hospitalized COVID-19 patients in the largest dataset to our knowledge to date using data from as recent as December 2020. Our study showed an increase in the use of treatments over time as well as decreases in ICU use and modest decreases in mortality, except for those receiving IMV/ECMO or HFO/NIV at baseline. Because of the recent emergence of COVID-19, conditions are rapidly evolving, and these studies must be repeated and account for temporal changes over the course of the study, a changing treatment landscape including vaccinations, while also controlling for differences in disease severity to understand the potential treatment benefit of new treatments whether as a single regimen or as a combination.

The COVID-19 Pandemic: A Comprehensive Review of Taxonomy, Genetics, Epidemiology, Diagnosis, Treatment, and Control

Remdesivir-based therapy improved recovery of patients with COVID-19 in the SARSTer multicentre, real-world study

World Health Organization. Weekly epidemiological update-2

Variation in US Hospital Mortality Rates for Patients Admitted With COVID-19 During the First 6 Months of the Pandemic

Trends in COVID-19 Risk-Adjusted Mortality Rates

Trends in mortality of hospitalised COVID-19 patients: A single centre observational cohort study from Spain. The Lancet Regional Health -Europe

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19

Ly-CoV555 Study Group. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19

Dexamethasone in Hospitalized Patients with Covid-19

Role for Anti-Cytokine Therapies in Severe Coronavirus Disease

COVID-19 Investigational Treatments in Use Among Hospitalized Patients Identified Through the US Coronavirus Disease 2019-Associated Hospitalization Surveillance Network

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial

Remdesivir for the Treatment of Covid-19 -Final Report

FDA Approval of Remdesivir -A Step in the Right Direction

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

Remdesivir (Veklury) package insert

Covid-19: Remdesivir is recommended for authorisation by European Medicines Agency

Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US

Patients with COVID19 Hospitalized Across the United States

Management and outcomes of patients hospitalized with severe COVID-19 at a tertiary care center in midwestern United States

Pharmacotherapy for Hospitalized Patients with COVID-19: Treatment Patterns by Disease Severity

Outcomes and Mortality Among Adults Hospitalized With COVID-19 at US Medical Centers

Uptake and Accuracy of the Diagnosis Code for COVID-19 Among US Hospitalizations

A c c e p t e d M a n u s c r i p t 17 A c c e p t e d M a n u s c r i p t 20