key: cord-0772593-oghn4ga9
authors: Khera, Rohan; Liu, Yusi; de Lemos, James A; Das, Sandeep R; Pandey, Ambarish; Omar, Wally; Kumbhani, Dharam J; Girotra, Saket; Yeh, Robert W; Rutan, Christine; Walcoch, Jason; Lin, Zhenqiu; Bradley, Steven M; Velazquez, Eric J; Churchwell, Keith B; Nallamothu, Brahmajee K.; Krumholz, Harlan M; Curtis, Jeptha P
title: Association of Coronavirus Disease-19 Hospitalization Volume and Case Growth at United States Hospitals with Patient Outcomes
date: 2021-07-31
journal: Am J Med
DOI: 10.1016/j.amjmed.2021.06.034
sha: b2a32993f6859eb556a3271ce7f15c3536d8da1d
doc_id: 772593
cord_uid: oghn4ga9

BACKGROUND: Whether the volume of coronavirus disease-19 (COVID-19) hospitalizations is associated with outcomes has important implications for the organization of hospital care both during this pandemic and also future novel and rapidly evolving high-volume conditions. METHODS: We identified COVID-19 hospitalizations at US hospitals in the American Heart Association COVID-19 Cardiovascular Disease Registry with ≥10 cases between January and August 2020. We evaluated the association of (1) COVID-19 hospitalization volume and 2) weekly case growth indexed to hospital bed capacity, with hospital risk-standardized in-hospital case-fatality rate (rsCFR). RESULTS: There were 85 hospitals with 15329 COVID-19 hospitalizations, with a median hospital case volume was 118 (IQR, 57, 252) and median growth rate of 2 cases/100 beds/week but varied widely (IQR: 0.9 to 4.5). There was no significant association between overall hospital COVID-19 case volume and rsCFR (rho, 0.18, P = 0.09). However, hospitals with more rapid COVID-19 case-growth had higher rsCFR (rho, 0.22, P = 0.047), increasing across case growth quartiles (P-trend, 0.03). While there were no differences in medical treatments or ICU therapies (mechanical ventilation, vasopressors), the highest case growth quartile had 4-fold higher odds of above median rsCFR, compared with the lowest quartile (OR, 4.00; 1.15 to 13.8, P = 0.03). CONCLUSIONS: An accelerated case growth trajectory is a marker of hospitals at risk of poor COVID-19 outcomes, identifying sites that may be targets for influx of additional resources or triage strategies. Early identification of such hospital signatures is essential as our health system prepares for future health challenges.

The coronavirus disease-19 pandemic challenged hospitals to adapt their care processes for a novel disease process with an unknown trajectory. Simultaneously, hospitals were also been overwhelmed by a disease that poses a substantial threat to healthcare resources, such as ICU and ventilator capacity, 1,2 and puts the healthcare workforce at personal health risk. 3 Therefore, while hospitals caring for COVID-19 patients gained institutional knowledge and experience that may help improve patient outcomes, a surge of patients that overwhelms available resources might impact care negatively. In this respect, care for COVID-19 differs from care for other conditions, where consistently hospitals with more experience demonstrate better outcomes, especially for new areas of care. [4] [5] [6] [7] Thus far, the assessment of COVID-19 outcomes has focused on patient features that portend adverse outcomes. [8] [9] [10] [11] [12] However, how hospitals responded to COVID-19 represents an important avenue into evaluating whether our care processes are designed to be resilient to large and dynamic case volumes of acute illnesses and can achieve similar outcomes despite these pressures. The knowledge gained from understanding these associations of volumes and outcomes for COVID-19 can inform care processes such as regionalization of care and sharing of resources across health systems as our health system continues to adapt to the COVID-19 pandemic and considers preparation for future health crises and challenges.

In a nationwide registry of hospitalized COVID-19 patients, we evaluated two distinct aspects of the experience of hospitals with COVID-19 case volumes. We assessed the overall case volumes at each participating hospitala commonly used metric for volume-outcome studies -and assessed for its association with survival to discharge after accounting for patient and hospital features. In addition, we constructed a novel case growth measure that accounted for rate of growth of COVID-19 as a function of hospital bed capacity, to assess whether rapid acceleration of COVID-19 case volumes relative to hospital capacity was associated with outcomes.

We used patient and hospital data from the American Heart Association (AHA) COVID-19 Cardiovascular Disease (CVD) Registry. The registry was designed to collect high quality information on patient characteristics and outcomes leveraging the Get With The Guidelines (GWTG) infrastructure in place for collecting data for AHA registries. 8, 13 The registry includes data from patients with completed hospitalizations for COVID-19 at participating hospitals defined by a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) polymerase chain reaction or an antigen test, and a clinical presentation consistent with COVID-19. The online data entry process ensured completeness of records and consistency in data fields across centers through internal logic checks. The current analysis is based on a data release that includes hospitalizations through August 2020 and captures hospitalizations in the early phase of the pandemic. Because the registry is designed as a quality improvement tool, with no intervention or participant contact, and collection of only a limited data set, informed consent is not obtained. The Duke University Institutional Review Board provided approval.

Hospitals represented the unit of the analysis and all hospitals with at least 10 COVID-19 cases were included. All COVID-19 cases reported from these hospitals were included. Two exposures were defined. First, overall COVID-19 case volume was defined as the absolute number of COVID-19 hospitalizations at individual hospitals across the same reporting period. The overall case volume represents the most commonly used unit of analyses in volume-outcome assessments. 7, 14, 15 Second, to specifically isolate the potential effect of rapid case growth at hospitals, we constructed a novel measure of case growth rate as a function of a hospital's total bed capacity. This case growth rate was defined as the average weekly change in the proportion of hospitalized COVID-19 patients relative to hospital bed number, beginning with the week when the first case was recorded and ending the week with the peak case load at the hospital across the study period (eFigure 1). The weekly hospital census of COVID-19 cases was based on hospital admission and discharge dates and included all patients who had a COVID-19 hospitalization spanning a given calendar week.

To ensure our analyses compared similar patients presenting to similar hospitals, we identified detailed patient and hospital characteristics. For patients, these included demographics and comorbid health conditions (eMethods). Further, in-hospital care features of intensive care unit (ICU) care and mechanical ventilation or renal replacement therapy were included. We identified several hospital characteristics including teaching status, census region, number of hospital beds, and average daily patient census in 2019 that were available from the American Hospital Association data merged with the AHA COVID-19 CVD registry.

The outcome of the study was hospital risk-standardized in-hospital mortality. This was computed using hierarchical models that accounted for patient and hospital characteristics. The construction of the model are described in eMethods and eTable 1 in the online supplement.

We classified hospitals into quartiles based on each of the two hospital volume exposures: overall hospital COVID-19 volume and hospital COVID-19 case growth. We compared characteristics of hospitals across these quartiles, including their location, teaching status, bed size, and average daily hospital census in the pre-COVID-19 era. Next, we evaluated differences in characteristics of patients across the hospital volume quartiles including demographics, comorbid conditions, and in-hospital care needs and treatments. To evaluate directional difference in characteristics across quartiles, we used the Cochran Armitage test for the categorical variables and Jonckheere-Terpstra trend test for continuous variables. We parametrized quartiles as an ordinal categorical variable from lowest to highest volume quartiles for these assessments.

To assess the association with mortality for each of the two exposures, we evaluated continuous associations between hospital case volumes and hospital risk-standardized mortality using Spearman correlation. Conceptually, these analyses quantified the differences in hospital rankings for risk-standardized mortality that could be ascribed to overall volumes or their case growth. We repeated an assessment of mean risk-standardized mortality across hospital quartiles of volume and case growth using linear regression with hospital quartiles parameterized as ordinal categories from lowest to highest.

We also calculated the odds ratio of above median risk-standardized mortality rates across volume and case growth quartiles with the lowest volume and case growth quartiles as referents, respectively.

To account for temporal evolution of care practices that may have potentially led to the observed improvements in patient outcomes over time, 16 and may confound volume-outcome assessments, we created a temporally restricted cohort for sensitivity analyses. In these analyses, we limited our assessment of both volume-outcome and case-growth-outcome relationships to hospitals that reached their case peak in the first half of the year, specifically before June 30, 2020.

The level of significance was set at 0.05. All analyses were performed using R 3.9 (R foundation, Vienna, Austria).

There were 104 hospitals with 15397 patients in the AHA COVID-19 CVD registry, of which 85 reported at least 10 COVID-19 cases and were included in the study. There were 15329 COVID-19 hospitalizations recorded at these hospitals during the study period. There was a large variation in volumes across hospitals, with median case volume of 118 (IQR, 57, 252) (Figure 1) . Hospitals in the highest case volume quartiles were larger, with larger bed size and average daily hospital census in the preceding year ( Table 1) . There were no significant differences in teaching status or urban or rural location across hospital quartiles of case volumes.

Patients in hospitals in the highest COVID-19 volume quartile were modestly younger (mean, 61.1 years in highest volume quartile vs 62.0 years in the lowest volume quartile), but without significant differences in either sex or race/ethnicity distributions or for cardiovascular and non-cardiovascular comorbidities ( Table 2 , P>0.05 for all comparisons). There were similarly no significant differences in proportions of patients receiving ICU care or those requiring mechanical ventilation, hemodialysis, or vasopressors. Lower volume hospitals had higher use of glucocorticoids but there was no difference in the proportion of patients receiving remdesivir, interleukin-6 (IL-6) antagonists or hydroxychloroquine across volume quartiles.

There was a large variation in patient mortality, with a median in-hospital case-fatality rate (CFR) of 14.3% (IQR 8.5%, 18 .7%) and risk-standardized case-fatality rate of 15.9% (12.5%, 20.0%) across hospitals. The median unadjusted inhospital CFR was 14.2% in the lowest volume quartile (Q1), 12.6% in Q2, 12.8% in Q3, and 16.8% in Q4. There was no significant association between overall COVID-19 case volume and risk-standardized CFR (spearman correlation, 0.18, P = 0.09) (Figure 2 ). Mortality was numerically higher but not significantly different across quartiles based on COVID-19 volumes, with median risk-standardized CFR of 15.5% (IQR 12.7%, 18.5%) in the lowest volume quartile and 18.2% (IQR, 14.9%, 21.5%, P for trend across quartiles, 0.34). Hospitals in the highest COVID-19 volume quartile had higher odds of having above median risk-standardized CFR compared with lowest volume quartile hospitals, however, these findings did not reach statistical significance (OR, 3.56; 95% CI, 0.99 to 12.7, P = 0.05).

The median COVID-19 hospitalizations case growth was 2 cases per 100 beds per week but varied widely (IQR: 0.9 cases/100 beds/week to 4.5 cases/100 beds/week) (Figure 1 ). There was a modest positive correlation between hospital case growth rate and total hospital COVID-19 volume (Spearman correlation coefficient, 0.22, P = 0.046). There were notable differences in hospital characteristics with large bed size and teaching hospitals less likely to be in the highest case growth rate quartile, even though they represented the largest group in the highest volume quartile (eTable 2). There were, however, no significant differences in patient characteristics across case-growth quartiles.

There was a significant positive correlation between case growth and risk-standardized hospital CFR, with hospitals with the most rapid case-growth having a significantly higher risk-standardized CFR (Spearman correlation coefficient: 0.22, P = 0.047) (Figure 3) . Median risk-standardized CFR was 13.9 (IQR 10.6%, 17.2%) in the lowest case growth quartile and 17.8% (IQR, 14.1%, 21.5%, P for trend across quartiles, 0.03). Hospitals in the highest case growth quartile had 4-fold higher odds of having above median risk-standardized CFR, compared with hospitals in the lowest case growth quartile (OR, 4.00; 95% CI, 1.15 to 13.8, P = 0.03).

In analyses that restricted the assessment of volumes and outcomes to early part of the pandemic, a total of 70 hospitals that had a peak case volume in June or earlier were included. Among these hospitals, there was a significant correlation between hospital volumes and hospital risk-standardized CFR (Spearman correlation coefficient, 0.32, P = 0.008). Among hospitals with an early case peak, those in the highest volume quartile had 11-fold higher odds of above median riskstandardized CFR (OR 11.43, 95% CI 1.97, 66.36, P = 0.007). Hospitals in the highest quartile of case growth who reached their peak volumes in the first half of the year had over 4-fold higher odds of above median risk-standardized CFR (OR 4.67; 95% CI, 0.96, 22.79, P = 0.057) similar to the primary analyses, but did not reach our predefined threshold of significance.

In a large nationwide registry of 85 hospitals with 15329 confirmed COVID-19 hospitalizations and detailed phenotypic characterization, there was a large variation in both the overall volume of COVID-19 cases as well as the trajectory of case growth. Hospitals had a large variation in patient mortality, even after accounting for differences in patient and hospital characteristics. The overall volume of COVID-19 cases at hospitals was not significantly associated with inhospital CFR, but in analyses of hospitals with early peaks in COVID-19 volumes, higher COVID-19 volume was associated with higher risk standardized CFR. We also found that the rate at which hospitals experienced an increase in their cases relative to their capacity across the study period was significantly associated with CFR, with faster rise in cases associated with higher risk-standardized CFR.

The challenges faced by hospitals in the COVID-19 pandemic have consistently been interpreted in light of their bed capacity and/or the vulnerability of their healthcare providers. However, from a patient outcomes perspective, in addition to volume, the rapidity with which a hospital experiences an increase in their case volume likely has important implications for patients receiving care at those hospitals. Hospital case growth and overall case volumes may potentially create a challenge for staffing, bed capacity, and ICU care needs, 17 which are frequently in flux due to the hazard for infection among healthcare workers. Despite this uncertainty about the mechanism, case growth, which can be assessed prospectively, may play a role in identifying hot spots that may benefit from an urgent influx of additional personnel and resources to care for the surge.

These observations also identify a potential explanation for the observed variation in risk-adjusted outcomes across hospitals that has been suggested in prior studies, 12, 16 especially since this variation in hospital outcomes cannot be explained by differences in measured patient characteristics. Of note, a recent study that addressed variation in outcomes across hospitals included individuals from a single payer and did not have the entire census of hospitalized COVID-19 patients, as was possible in our study using an all-comer registry. 16 While larger hospitals had higher case volumes, there was no correlation of COVID-19 volumes with patient comorbidities or illness severity based on the need for ICU care.

Moreover, volume itself is an imperfect surrogate for burden, as has been observed in care for acute cardiovascular conditions and cardiovascular surgery. 7, 14, 15, 18 Our hypothesis-driven metric that captures the rate of case growth as a function of a hospital's capacity may offer a more nuanced and accurate assessment of burden on hospitals. Further, our findings may explain the high CFR for certain patient groups in communities with high incidence of COVID-19 infections, 9, 12, 19 as we find that racial/ethnic minorities more frequently presented to hospitals that were more rapidly approaching their capacity. These hospitals may be ideal sites for interventions aimed at reducing mortality from COVID-19 potentially through regionalization of care and sharing of staff and resources to allow continued high-quality supportive care. Further, interventions that decrease hospital length of stay, [20] [21] [22] in addition to other outcomes, may have a role in improving the hospital census and the overwhelming of capacity by rapid case growth.

Our study has certain limitations. First, our observations are limited to hospitals participating in the AHA COVID-19 CVD registry and may not be representative of all US community hospitals. However, the registry has specifically included geographically dispersed hospitals across bed capacity strata. Second, the participation of the hospitals was voluntary, and they have not yet been subject to an audit ensuring all cases were reported. However, the data entry platform was based on a familiar infrastructure that is used by other registries by the AHA in its broader Get With The Guidelines program. Third, we modelled hospital volumes using two standards, but there could be other unsupervised models that better capture the trajectory of the curves for each hospital's case volume. However, as we hoped to gain actionable insights from this study, we applied either existing or hypothesis-driven strategies to the choice of our exposures.

Nevertheless, a better understanding of the entirety of the case volume trajectory may offer additional insights about the effect of case volumes on patient outcomes. Fourth, the registry included data through August, and the case-growth patterns in the most recent winter peak of COVID-19 cases and its association with outcomes may differ.

Fifth, there could be unmeasured variation in patient features, including income and education, that are not accounted for in the models. However, our risk-adjustment models were robust and had a model discrimination of 0.73 at a patient-level, suggesting successful capture of patient features that predicted outcomes. We also did not find a significant difference in patient characteristics across hospitals based on their case volumes or their use of drug therapies.

Moreover, while there appear to be patterns in sensitivity analyses suggestive of a stronger volume-outcome relationship during the early part of the pandemic, we were limited by statistical power in subsetting the time period into smaller units.

Sixth, we did not capture outcomes of patients after hospital discharge, limiting our ability to assess overall case fatality rates for hospitalized patients. Finally, the case volumes and case growth do not explain the majority of variation in outcomes across hospitals, which requires dedicated investigation into differences in other hospital care practices.

In conclusion, an accelerated case growth trajectory is a marker of hospitals at risk of poor COVID-19 outcomes.

These sites may be targets for influx of additional resources or triage strategies. Early identification of such hospital signatures that may portend poor outcomes is essential as our health system prepares for future health challenges.

Authors had access to the data from the American Heart Association. The study was conceived by R.K., its design was discussed among all authors. R.K. and Y.L. conducted the analyses. R.K. drafted the manuscript, which was reviewed and critical input was provided by all authors.

Dr. Khera received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health under the grant 1K23HL153775. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 

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Average Weekly Case Growth Slope Across Hospitals in the AHA COVID-19 CVD Registry. The units of the y-axis are number of cases in (A) and case increase per 100 beds per week in (B) and represents the average weekly case growth from the week of first case to that of the peak case volume. The x-axis represents individual hospitals ordered by their case volumes in (A) and their case-growth slope

Hospital Case-Growth Slope

Figure 2. Correlation Between COVID-19 Hospitalization Volume and Risk-Standardized In-hospital Case-Fatality Rate. Spearman correlation for hospital volume and risk-standardized mortality is 0.18, P = 0.09. Labelled points represent risk-standardized inhospital case-fatality rate for the median hospital based on volume in each quartile

CRRT, continuous renal replacement therapy

CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention

ILD, interstitial lung disease; MI, myocardial infarction

TIA, transient ischemic attack *P-value for Jonckheere-Terpstra trend test

We thank Laura Stevens and Julie Sizelove of the American Heart Association (AHA) for their assistance in gaining access to the AHA COVID-19-CVD registry and the Precision Medicine Platform.