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\begin{document}

\title{Clinical Outcomes of COVID-19 Treated with Remdesivir Across the
Continuum of Care}



\author[1]{Christina Rivera}%
\author[1]{Supavit  Chesdachai}%
\author[1]{Evan  Draper}%
\author[1]{Richard  Arndt}%
\author[1]{Kristin C.  Mara}%
\author[1]{Maria  Gonzalez Suarez}%
\author[1]{ Raymund  Razonable}%
\affil[1]{Mayo Clinic}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Introduction: During the early phase of the coronavirus disease 2019
(COVID-19), remdesivir was only approved for hospitalized patients. Our
institution developed hospital-based, outpatient infusion centers for
selected hospitalized patients with COVID-19 who had clinical
improvement to allow for early dismissal. The outcomes of patients who
transitioned to complete remdesivir in the outpatient setting were
examined. Methods: Retrospective study of all hospitalized adult
patients with COVID-19 who received at least one dose of remdesivir from
11/6/2020 to 11/5/2021 at one of the Mayo Clinic hospitals. Results:
Among 3,029 hospitalized patients who received treatment with remdesivir
for COVID-19, the majority (89.5\%) completed the recommended the
five-day course. Among them, 2,169 (80\%) completed treatment during
hospitalization, while 542 (20.0\%) patients were dismissed to complete
remdesivir in outpatient infusion centers. Patients who completed the
treatment in the outpatient setting had lower odds of death within 28
days (aOR 0.14, 95\% CI 0.06-0.32, p\textless{}0.001). However, their
rate of subsequent hospital encounters within 30 days was higher (aHR
1.88, 95\% CI 1.27-2.79, p=0.002). Among patients treated with
remdesivir only in the inpatient setting, the adjusted odds of death
within 28 days were significantly higher among those who did not
complete the 5-day course of remdesivir (aOR 2.07, 95\% CI 1.45-2.95,
p\textless{}0.001). Conclusions: This study describes the clinical
outcomes of a strategy of transitioning remdesivir therapy from
inpatient to outpatient among selected patients. Mortality was lower
among patients who completed the 5-day course of remdesivir.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus
that causes coronavirus disease 2019 (COVID-19), continues to cause
morbidity and mortality globally.\textsuperscript{1} Evidence-supported
treatment for COVID-19 include small molecule antiviral drugs,
anti-spike neutralizing monoclonal antibodies and immunomodulatory
agents.\textsuperscript{2} Remdesivir, a direct-acting nucleotide
inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase, was the first
antiviral drug approved for clinical use, and remains as backbone for
treatment of hospitalized patients with COVID-19.\textsuperscript{3-5}

Remdesivir has been demonstrated to be effective for treatment of
hospitalized patients with severe disease and high-risk outpatients with
mild COVID-19. A phase 3 trial showed that a 5-day course of remdesivir
shortened recovery time among hospitalized patients with
COVID-19.\textsuperscript{4,6,7} {[}4, 6, 7{]}. Among non-hospitalized
outpatients with conditions that predisposes to severe disease
progression, a 3-day course of remdesivir reduced the rates of
hospitalization or death by 87\% compared to placebo.\textsuperscript{8}

Prior to 2022, remdesivir was only approved for clinical use in hospital
settings.\textsuperscript{9} At the Mayo Clinic, most patients remained
hospitalized for a minimum of 5 days to complete the course of
remdesivir treatment. Patients who improved clinically often expressed
desire to leave the hospital prior to completion of the 5-day course of
remdesivir. However, the outcome of the abbreviated course of remdesivir
was not known. In November 2021, our program developed hospital-based
infusion therapy centers to allow for earlier dismissal of hospitalized
patients who had achieved clinical improvement. By allowing early
dismissal of stable improving hospitalized patients, the healthcare
system would benefit by making hospital rooms and staff available for
sicker patients.

In this study, we report the outcomes of patients with COVID-19 treated
with remdesivir across the continuum of care. We aim to describe the
characteristics and outcomes of patients who were transitioned to
complete remdesivir in the hospital-based outpatient setting and assess
their risk of mortality and 28-day re-admission rates.

\textbf{Methods}

Study design and patient population

This is a retrospective multi-site cohort study of adult patients during
a one-year period from 11/6/2020 to 11/5/2021. All patients were
admitted to one of the Mayo Clinic hospitals with COVID-19 diagnosis and
received at least one dose of intravenous remdesivir. Per our standard
practice, all patients hospitalized for COVID-19 were assessed for
eligibility for a 5-day remdesivir course in the inpatient setting.

For this study, the patients were categorized into those who: 1)
completed the 5-day remdesivir course entirely inpatient, 2) completed
remdesivir course after transitioning to the outpatient setting, 3) did
not complete remdesivir course but remained inpatient, and 4) did not
complete remdesivir after discharge from the hospital. Determination of
inpatient or outpatient status was based on patient classes, department,
and manual review when unable to determine by other methods. Remdesivir
treatment course was categorized as incomplete if \textless{}5 doses or
\textless{}600 mg total was documented in the medication administration
record.

Patients were eligible for this study if they were [?]18 years of age and
received a first course of remdesivir. If there were \textgreater{}2
calendar days between doses of remdesivir, these were considered
separate courses and the subsequent course(s) were excluded. Other
exclusion criteria included receipt of an anti-spike neutralizing
monoclonal antibody or convalescent plasma, use of remdesivir under
another study protocol, and patients transitioning from an outside
facility during remdesivir treatment. Minnesota residents who declined
research authorization were excluded. The Mayo Clinic Institutional
Review Board deemed this study to be exempt.

Clinical variables and outcomes

All-cause mortality was defined as death within 28 days of the first
dose of remdesivir. Death related to COVID-19 was determined by chart
review by study team physician or clinical pharmacist. Second review was
performed by study physician if cause of death was unable to be
determined by clinical pharmacist.

Liver function tests (LFT, alanine and aspartate aminotransferases) were
reviewed for 10 days from the start of remdesivir treatment. Body mass
index (BMI), World Health Organization (WHO) ordinal scale, Monoclonal
Antibody Screening Score (MASS), and use of steroids, baricitinib, or
tocilizumab were collected. MASS is a clinical risk prioritization score
for the allocation of anti-spike monoclonal antibodies, and includes
age, body mass index, chronic heart, kidney and lung diseases, diabetes
mellitus, hypertension, pregnancy and an immunosuppressed condition or
treatment.\textsuperscript{10} Primary diagnosis code was used to
identify hospital and emergency care encounters related to COVID-19
within 30 days of the last administered dose of remdesivir and long
COVID related encounters within 180 days.

Statistical analysis

Data are summarized using medians and interquartile ranges (IQR) for
continuous data and frequencies and percentages for categorical data.
Patient characteristics were compared between groups using
Kruskal-Wallis tests for continuous data and either Chi-square or
Fisher's exact tests for categorical data. Multivariable logistic
regression was used to assess associations between treatment group and
the outcomes of having an abnormal LFT, all-cause mortality within 28
days, and death related to COVID-19 within 28 days of remdesivir
treatment initiation after adjusting for age, sex, and MASS score. Rates
of subsequent ED visit or hospitalization within 30 days and subsequent
long COVID encounters within 180 of remdesivir initiation were estimated
using the Aalen-Johansen method, where death was considered a competing
risk. Cox proportional hazards regression was used to assess the
associations between these outcomes and treatment groups. Pairwise
comparisons between groups were adjusted for multiple comparisons using
the false discovery rate method. All analyses were performed using SAS
version 9.4 software (SAS Institute, Inc; Cary, NC).

\textbf{Results}

Clinical characteristics of the study population

The study population consisted of 3,029 patients who were hospitalized
and received at least one dose of remdesivir for COVID-19 during the
one-year study period. The median age was 67 years {[}IQR 55, 77{]};
1,293 (42.7\%) were female and 2,684 (88.6\%) were white. Median BMI was
31 {[}IQR 27, 37{]} kg/m\textsuperscript{2}. The median MASS was 3
{[}IQR 2, 6{]}. Most common medical comorbidities were hypertension
(38.1\%), cardiovascular disease (33.6\%) and diabetes mellitus
(31.7\%).

Systemic steroids and other immunomodulators (baricitinib or
tocilizumab) were used in 2,384 (78.7\%) and 381 (12.6\%) patients,
respectively. Most patients (84.1\%) required oxygen supplementation, as
follows: 1,373 (45.3\%) by nasal cannula, 829 (27.4\%) by high-flow
nasal cannula or non-invasive positive-pressor ventilator support, 152
(5.0\%) by mechanical ventilator, and 5 (0.2\%) by extracorporeal
membrane oxygenation (ECMO). The details of the demographic and other
clinical characteristics of patients are in \textbf{Table 1} .

Overall outcomes of the study population

Two hundred and sixty-five (8.7\%) patients died within 28 days of
starting remdesivir; 219 (82.6\%) were COVID-19 related. Older age was
significantly associated with higher rates of all-cause and COVID-19
related deaths (\textbf{Table 2} ). Higher all-cause and COVID-19
related death was also observed among patients who did not complete the
5-day course of remdesivir (\textbf{Figure 1} ). Patients who improved
clinically and were dismissed to complete the remdesivir course in the
outpatient setting had a lower risk of all-cause and COVID-19 related
death (\textbf{Table 2} ).

Among patients who survived during the COVID-19 hospitalization, 141
(5.1\%) patients had subsequent ED visits or re-admission within 30
days. There was a higher rate of ED visits and re-admissions within 30
days among patients who were dismissed prior to completion of 5 days of
remdesivir (\textbf{Table 2} ). Twenty-two (0.8\%) patients had
healthcare encounters due to long COVID within 180 days.

Characteristics and outcomes of patients who completed remdesivir
inpatient versus those who were transitioned to the outpatient setting

Of 3,029 patients, the majority (2,711; 89.5\%) completed the remdesivir
for a total of 5 days. Among 2711 patients, the majority (n=2,169
{[}80\%{]}) completed the 5 days of remdesivir during hospitalization
while 542 patients (20.0\%) were dismissed early and transitioned care
to complete remdesivir in the outpatient setting. There was a total of
1,077 doses of remdesivir infused in hospital-based outpatient infusion
centers.

Patients transitioned to complete the remdesivir course as an outpatient
were significantly younger than those who remained hospitalized (median
age, 61 {[}IQR 48, 72{]} versus 69 {[}IQR 57, 79{]}; p\textless{}0.001),
and they had significantly lower number of comorbidities, as shown by
MASS (median MASS 3 {[}IQR 1, 5{]} versus 4 {[}IQR 2, 6{]};\emph{p}
\textless{}0.001). The proportion of patients who required oxygen
supplementation and systemic corticosteroids and immunomodulators were
significantly higher among patients who remained in the inpatient
setting (\emph{p} \textless{}0.001). Abnormal liver tests were observed
more often among patients who remained in the hospital (n=1,315
{[}60\%{]}) compared to those transitioned to the outpatient setting
(n=231 {[}42.6\%{]}).

The 28-day mortality rate was 9.7\% (n=211 patients) and 0.9\% (n=5
patients) for the inpatient and outpatient groups, respectively.
Adjusting for age, sex and MASS, the outpatient groups had lower odds of
death within 28 days (adjusted Odd Ratio (aOR) 0.14, 95\% confidence
interval (CI) 0.06-0.32, \emph{p} \textless{}0.001). However, the rate
of subsequent ED visits or re-admission within 30 days was significantly
higher in patients dismissed early to complete the remdesivir course in
the outpatient setting (adjusted Hazard Ratio {[}aHR{]}: 1.88, 95\% CI
1.27-2.79, \emph{p} =.002) (\textbf{Table 2} ). After excluding those
who died in the hospital, there was no significant difference in the
odds of death within 28 days between two groups (aOR: 0.69, 95\% CI
0.28-1.68,\emph{p} =0.41), but the rate of ED visits or re-admission
within 30 days remained higher in the outpatient cohort (aHR: 1.75, 95\%
CI 1.15-2.64,\emph{p} =0.009) (\textbf{Supplemental Table 1} ).

Characteristics and outcomes of patients who completed versus did not
complete remdesivir during hospitalization

Of 3,029 patients, the majority (n=2465 {[}81.4\%{]}) received
remdesivir only in the hospital setting. Among these 2465 patients, 296
(12.0\%) did not complete the recommended 5-day course of remdesivir in
the hospital (or in the outpatient setting). Twenty-two of 296 (7.4\%)
patients did not complete remdesivir because they died within five days
after starting treatment.

There were no statistically significant differences in age, sex, and
MASS between the inpatients who did and did not complete remdesivir in
the hospital. However, the proportion of patients who required oxygen
supplementation and received steroids or immunomodulators were
significantly higher among patients who completed the remdesivir course
for 5 days (\emph{p} \textless{}0.001).

The adjusted odds of abnormal liver panel were lower among hospitalized
patients who did not complete versus those who completed the 5-day
course of remdesivir (aOR 0.56; 95\% CI 0.43-0.72,\emph{p}
\textless{}0.001). There was no significant difference in subsequent ED
visits or re-admission within 30 days, but the adjusted odds of 28-day
mortality was two-fold higher among patients who did not complete
remdesivir in the hospital (aOR 2.07, 95\% CI 1.45-2.95,\emph{p}
\textless{}0.001) (\textbf{Table 2} ). The results were similar, after
excluding the patients who died in the hospital (\textbf{Supplemental
Table 1} ).

Characteristics and outcomes of dismissed patients who completed versus
did not complete remdesivir in the outpatient setting

A total of 564 patients were dismissed from the hospital prior to
completion of the 5-day course of remdesivir. Among them, 22 (0.7\%)
patients received at least one dose of outpatient remdesivir but did not
complete the full 5-day course. There were no statistically significant
differences in the clinical characteristics between patients who
completed versus those who did not complete outpatient remdesivir.

The all-cause and COVID-19 mortality among 22 patients who did not
complete the remdesivir course in the outpatient setting was similar to
those who remained hospitalized for the 5-day course of remdesivir. In
contrast, the all-cause and COVID-19 mortality among those who completed
the 5-day course of remdesivir in the outpatient was lower than those
who remained in the hospital (\textbf{Table 2} ).

\textbf{Discussion}

This retrospective study of a large cohort of hospitalized patients with
COVID-19 treated with remdesivir in a large healthcare system highlights
several noteworthy observations. First, one in five hospitalized
patients with COVID-19 improved clinically prior to completion of the
5-day course of remdesivir treatment. Second, there was a higher rate of
hospital re-admission or ED visit among those who were dismissed prior
to completion of the standard 5-day course of remdesivir. Third,
mortality at day 28 was associated with older age and having not
completed the 5-day course of remdesivir. As the COVID-19 pandemic
established endemicity worldwide, our clinical observations have
potential applications in its management across the continuum of care
settings.

Our study examined all hospitalized patients with COVID-19 treated with
remdesivir from November 2020 to November 2021, a period that
encompasses the pre-vaccination period to the sequential roll out of
vaccines to eligible patients.\textsuperscript{11,12} Among our cohort
of \textgreater{}3,000 patients, the mortality rate was 8.7\%; this
reflects the high-risk characteristics of our population. Our patients
are predominantly older (56\% are older than 65 years old) and had
multiple medical comorbidities (as measured by MASS). Hypertension,
cardiovascular disease and diabetes were the most common underlying
conditions. While medical comorbidities have been associated with severe
outcomes from COVID-19, an older age was the most significant risk
factor for all-cause and COVID-19 related death in this
study.\textsuperscript{13} The significant association between older age
and severe outcome from COVID-19 is well
described.\textsuperscript{14-16} Since the conduct of our study, there
has been increasing rates of vaccination among the population, while
treatment options have expanded to reduce the risk of death and severe
disease from COVID-19.

In our cohort, one in five patients who required hospitalization for
COVID-19 improved early prior to completion of the standard 5-day
remdesivir treatment. This is a novel observation that has important
clinical, operational and logistical implications. During the different
waves of the COVID-19 pandemic, especially during the SARS-CoV-2 Delta
wave, healthcare systems were overburdened with high number of patients
requiring medical care in the hospital. This resulted in a shortage of
medical beds and staff to care for the sick hospitalized patients. In
this situation, one wonders if patients who have improved but have not
yet completed the remdesivir course could be safely dismissed from the
hospital. Because of the uncertainty of their outcomes, our program
established hospital-based outpatient infusion centers to allow for
hospital dismissal of stable and improving patients yet provided the
infrastructure to complete the treatment course. This strategy is akin
to well-established outpatient antimicrobial therapy (OPAT) programs,
where intravenous antibiotics are administered in infusion units outside
the hospital settings. As a result of this practice, we estimated a
total of 1077 hospital rooms that were made available to other patients
needing critical services in the hospital.

This study observed that the rate of death by day 28 among patients who
did not complete 5-day course of remdesivir were higher compared to
those who completed the treatment course. In particular, patients who
did not complete remdesivir course in the hospital and did not receive
additional dose of remdesivir as an outpatient had three-time higher
odds of death within 28 days compared to patients who completed the
treatment course. Our findings imply that completion of a planned 5-day
course of remdesivir is crucial to improving outcomes. Physical and
electronic infrastructures to ensure the administration of intravenous
remdesivir in the outpatient setting is therefore important. The
implementation of our strategy was intertwined with the establishment of
the Monoclonal Antibody Treatment (MATRx) Program in November
2020.\textsuperscript{17} Since the infrastructure of outpatient
remdesivir infusion was operational since November 2020, it was an easy
transition for our program to provide remdesivir as an approved option
for outpatients with mild to moderate COVID-19. Our program have used
the three-day outpatient remdesivir course especially among those with
contraindications to ritonavir-boosted nirmatrelvir and when there is
scarcity of effective anti-spike neutralizing monoclonal
antibodies.\textsuperscript{10}

Despite the benefits of early dismissal (by allowing patients to recover
in the comfort of their home environment), it is important to point out
that there was a higher rate of re-admissions or ED visits among
patients who were dismissed early to complete remdesivir in the
outpatient setting. While it is possible that clinically improving
patients have been prematurely dismissed, the biphasic course of
COVID-19 could have prompted patients to seek further care when their
symptoms rebounded.\textsuperscript{18} This data further calls into
question the assumptions that patients with COVID-19 selected for
hospital dismissal are well enough that ongoing medical care, including
medication therapy, is unneeded. It is therefore important to remotely
monitor these patients at home, in order to capture early warning signs
that would require further medical intervention.\textsuperscript{19} It
will also be important to further characterize these patients and define
risk factors for re-admissions in order to mitigate the need for further
medical evaluations.

There are several limitations of this study. First, it is a
retrospective study with inherent deficiencies in capturing all
clinically relevant information for all patients. Second, the cohort was
stratified patients into four groups, with varying demographic and
clinical characteristics. We attempted to adjust for them in the
multivariable analysis. Third, the findings may only apply to healthcare
systems with the infrastructure that allows for the safe administration
of remdesivir in the outpatient setting. While our program adapted this
novel strategy in conjunction with the implementation of anti-spike
monoclonal antibody infusion, the logistics of scheduling once daily
doses of remdesivir for patients was challenging (but not impossible) to
implement. It will be important to assess the economic impact of this
practice as well as patient perception and satisfaction of this strategy
of care.

This study of over 3000 patients hospitalized for COVID-19 highlights
the importance of completing a 5-day course of remdesivir treatment.
Older age was significantly associated with a higher risk of death,
while completion of the full course of remdesivir was associated with
lower risk of death. Among patients who have improved clinically to
allow for early hospital dismissal, it is important to ensure that they
complete their treatment course in the outpatient setting. This novel
strategy of transitioning remdesivir treatment among hospitalized
patients from inpatient to the outpatient setting appears to be
associated with clinical benefits, in addition to decongesting an
overburdened hospital system. This strategy could be implemented
selectively among stable patients, especially when hospitals are
overburdened with a census exceeding their capacity for care.

\textbf{References}

{[}1{]} Barouch DH. Covid-19 Vaccines --- Immunity, Variants, Boosters.
New England Journal of Medicine 2022;387(11):1011-20.

{[}2{]} Bhimraj A MR, Shumaker AH, Baden L, Cheng VC, Edwards KM,
Gallagher JC, Gandhi RT, Muller WJ, Nakamura MM, O'Horo JC, Shafer RW,
Shoham S, Murad MH, Mustafa RA, Sultan S, Falck-Ytter Y. Infectious
Diseases Society of America Guidelines on the Treatment and Management
of Patients with COVID-19. 2022.

{[}3{]} Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral
GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science
translational medicine 2017;9(396).

{[}4{]} Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the
Treatment of Covid-19 - Final Report. The New England journal of
medicine 2020;383(19):1813-26.

{[}5{]} Pan H, Peto R, Henao-Restrepo AM, et al. Repurposed Antiviral
Drugs for Covid-19 - Interim WHO Solidarity Trial Results. The New
England journal of medicine 2021; 384(6):497-511.

{[}6{]} Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe
COVID-19: a randomised, double-blind, placebo-controlled, multicentre
trial. Lancet (London, England) 2020;395(10236):1569-78.

{[}7{]} Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir
vs Standard Care on Clinical Status at 11 Days in Patients With Moderate
COVID-19: A Randomized Clinical Trial. Jama 2020;324(11):1048-57.

{[}8{]} Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to
Prevent Progression to Severe Covid-19 in Outpatients. New England
Journal of Medicine 2021;386(4):305-15.

{[}9{]} Rubin D, Chan-Tack K, Farley J, Sherwat A. FDA Approval of
Remdesivir --- A Step in the Right Direction. New England Journal of
Medicine 2020;383(27):2598-600.

{[}10{]} Razonable RR, Ganesh R, Bierle DM. Clinical Prioritization of
Antispike Monoclonal Antibody Treatment of Mild to Moderate COVID-19.
Mayo Clin Proc 2022;97(1):26-30.

{[}11{]} Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of
the mRNA-1273 SARS-CoV-2 Vaccine. New England Journal of Medicine
2020;384(5):403-16.

{[}12{]} Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of
the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine
2020;383(27):2603-15.

{[}13{]} Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. New England
Journal of Medicine 2020;383(25):2451-60.

{[}14{]} Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors
associated with COVID-19-related death using OpenSAFELY. Nature
2020;584(7821):430-6.

{[}15{]} Fisman DN, Bogoch I, Lapointe-Shaw L, McCready J, Tuite AR.
Risk Factors Associated With Mortality Among Residents With Coronavirus
Disease 2019 (COVID-19) in Long-term Care Facilities in Ontario, Canada.
JAMA Network Open 2020;3(7): e2015957-e.

{[}16{]} Harrison SL, Fazio-Eynullayeva E, Lane DA, Underhill P, Lip
GYH. Comorbidities associated with mortality in 31,461 adults with
COVID-19 in the United States: A federated electronic medical record
analysis. PLoS medicine 2020;17(9):e1003321.

{[}17{]} Razonable RR, Aloia NCE, Anderson RJ, et al. A Framework for
Outpatient Infusion of Antispike Monoclonal Antibodies to High-Risk
Patients with Mild-to-Moderate Coronavirus Disease-19: The Mayo Clinic
Model. Mayo Clin Proc 2021;96(5):1250-61.

{[}18{]} Ranganath N, O'Horo JC, Challener DW, et al. Rebound Phenomenon
after Nirmatrelvir/Ritonavir Treatment of Coronavirus Disease-2019 in
High-Risk Persons. Clin Infect Dis 2022; {[}published online ahead of
print{]} doi: 10.1093/cid/ciac481.

{[}19{]} Haddad TC, Coffey JD, Deng Y, et al. Impact of a High-Risk,
Ambulatory COVID-19 Remote Patient Monitoring Program on Utilization,
Cost, and Mortality: Mayo Clin Proc. 2022; {[}published online ahead of
print{]} doi: 10.1016/j.mayocp.2022.08.015.

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