Keywords anticoagulants - COVID-19 - hospitalization - risk factors - thromboembolism
Introduction
Coronavirus 2019 (COVID-19), an infectious disease caused by the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread throughout the world and overwhelmed
health care resources. Most COVID-19 cases result in mild symptoms, such as fever,
cough, fatigue, and shortness of breath; however, cardiovascular complications, including
arterial thromboembolism (ATE) and venous thromboembolism (VTE), have been observed.[1 ] A recent meta-analysis reported the prevalence of COVID-19–related ATE and VTE to
be 4.0% (95% confidence interval [CI]: 2.0–6.5%) and 14.7% (95% CI: 12.1–17.6%), respectively,
with a higher VTE prevalence reported in critically ill patients (23.2% [95% CI: 17.5–29.6%]).[2 ] A network cohort study found lower but similar 90-day cumulative incidence rates
for ATE and VTE among COVID-19 patients (0.1–0.8% and 0.2–0.8%), with increased rates
among those hospitalized (3.1 and 4.6%).[3 ]
Coagulopathy markers, including thrombocytopenia and elevated D-dimer, fibrin degradation
products, prothrombin time, and partial thromboplastin time, have been associated
with COVID-19 thromboembolic events and mortality.[4 ]
[5 ] SARS-CoV-2 infects endothelial cells through the angiotensin-converting enzyme 2
receptor, leading to thromboembolism.[4 ]
[6 ]
[7 ] Although the mechanistic understanding continues to evolve, preliminary reports
suggest that a complex interplay of inflammatory cytokines (e.g., interleukins [IL],
interferons, tumor necrosis factors, and endothelial cell dysfunction) triggers a
coagulation cascade leading to hemostatic abnormalities, intravascular coagulopathy,
formation of pulmonary microthrombi, and alteration of cardiac biomarkers and platelet
function.[6 ]
[8 ] In particular, the correlation between IL-6 and fibrinogen levels supports the theory
of inflammatory thrombosis.[9 ]
To understand the risk of ATE and VTE in patients with COVID-19, a risk profile composed
of characteristics, treatment journeys, and clinical outcomes among patients with
COVID-19 is essential. Three of four components of metabolic syndrome (hypertension,
diabetes, and hyperlipidemia) were associated with ATE in COVID-19 patients.[7 ] In addition, new-onset atrial fibrillation is common in patients with COVID-19,
occurring in 7.4% of patients in a large meta-analysis and may contribute to ATE.[10 ] Older age (≥65 years); active smoking; history of stroke; low and high body mass
index (BMI); and elevated D-dimer, platelet count, or C-reactive protein levels have
been shown to be risk factors for VTE in patients with COVID-19.[5 ]
[11 ]
[12 ]
[13 ]
[14 ] Moreover, patients in the intensive care unit (ICU) exhibit a distinct phenotype
that includes in situ pulmonary thrombosis more frequently than non-ICU patients.[15 ] Despite varying outcomes in ICU and non-ICU patients,[16 ] the American Society of Hematology,[17 ]
[18 ] American College of Chest Physicians,[19 ] National Institutes of Health,[20 ] and International Society on Thrombosis and Haemostasis[21 ] suggest using prophylactic anticoagulation in all hospitalized patients based on
low-quality evidence.[22 ]
[23 ] Guidelines published by the Global COVID-19 Thrombosis Collaborative Group[6 ] and the VAS-European Independent Foundation in Angiology/Vascular Medicine[24 ] consider risk factors, particularly comorbidities, in determining the need for VTE
prophylaxis. Early observational evidence suggests that prophylactic anticoagulation
was rapidly implemented in hospitalized patients with COVID-19, a step that was associated
with reductions in mortality.[25 ] Recently reported randomized trials support the use of therapeutic thromboprophylaxis
over standard thromboprophylaxis in medical ward COVID-19 inpatients, but not in those
with critical illness.[26 ]
[27 ]
[28 ]
Although evidence on the management of COVID-19–related symptoms is increasing, additional
knowledge is needed to inform the incidence of thromboembolic events in hospitalized
patients with COVID-19. Therefore, the primary objectives of this study were to evaluate
a large cohort of patients hospitalized with COVID-19 for demographic and clinical
characteristics, use of relevant anticoagulant and other medications, and occurrence
of thromboembolic events and all-cause mortality during and after hospitalization.
Methods
Data Source
This study was conducted using the longitudinal and low-latency Optum COVID-19 Electronic
Health Records (EHR) dataset. Leveraging the deidentified Optum EHR database, COVID-19
patients were included in this Optum COVID-19 EHR dataset based on COVID-19 diagnosis
codes and laboratory tests. All data elements in the Optum EHR database, including
patient demographics, outpatient visits, coded diagnostic procedures, medications,
laboratory results, hospitalizations, clinical notes, and patient outcomes from a
network of health care provider organizations across the United States, were included
in this COVID-19 dataset. As of January 7, 2021, there were 3.6 million patients in
this dataset.
Research Ethics
All study data were accessed with protocols compliant with U.S. patient confidentiality
requirements, including the Health Insurance Portability and Accountability Act of
1996. Because this study consisted of secondary data analyses of deidentified patient
records, the study did not constitute human subjects research and was exempt from
Institutional Review Board registration and review requirements under the U.S. Federal
Policy for the Protection of Human Subjects (also known as the “Common Rule”).
Study Design and Study Population
This retrospective, observational cohort study analyzed the Optum EHR data of adult,
hospitalized, COVID-19 patients for the 50-week period between January 21, 2020 and
January 7, 2021 (cohort identification period; [Fig. 1 ]).
Fig. 1 Study design for (A ) patients hospitalized with a diagnosis of COVID-19,a (B ) patients hospitalized with a diagnosis nonspecific for COVID-19,b and (C ) nonhospitalized COVID-19 patientsa,b who are hospitalized within 14 days for COVID-19. Examples of timelines are given,
noting that patients whose index dates were later in the cohort identification period
(e.g., November and December 2020) would have shorter available times for follow-up.
COVID-19, coronavirus 2019; ICD-10-CM, International Classicification of Diseases, 10th Revision, Clinical Modification . a Defined as ICD-10-CM: U07.1, B97.29, B97.21, or B34.2. b Defined as ICD-10-CM: J12.81, J12.89, J20.8, J22, J40, J80, J98.8, A41.89, R05, R06.02,
or R50.9.
Adult patients (age ≥18 years) who had a hospital admission on or after January 21,
2020 and fit into one of the following two scenarios were included in the study: (1)
having a coronavirus-related International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code (U07.1, B97.29, B97.21, B34.2) in any diagnosis position during
a hospitalization; AND a positive COVID-19–specific nonantibody laboratory test ([Supplemental Table S1 ]) within ± 14 days of the hospital admission date OR having a second hospitalization
with a diagnosis of COVID-19 (ICD-10-CM: U07.1, B97.29, B97.21, or B34.2) in any diagnosis
position within 14 days after the admission date of the first hospitalization ([Fig. 1A ]); OR (2) having a code nonspecific for COVID-19 (ICD-10-CM: J12.81, J12.89, J20.8,
J22, J40, J80, J98.8, A41.89, R05, R06.02, R50.9) in any diagnosis position AND a
positive COVID-19–specific nonantibody laboratory test ([Fig. 1B ] and [Supplemental Table S1 ]) within ± 14 days of the hospital admission date. These inclusion criteria were
used to ensure that the patients identified were truly hospitalized COVID-19 patients
given the uncertainty in testing, coding, and diagnosis at the beginning of the pandemic.
Nonhospitalized COVID-19 patients identified with a code for COVID-19 (ICD-10-CM:
U07.1, B97.29, B97.21, B34.2, J12.81, J12.89, J20.8, J22, J40, J80, J98.8, A41.89,
R05, R06.02, or R50.9) who were hospitalized for COVID-19 within 14 days following
the first outpatient COVID-19 diagnosis were reclassified as hospitalized COVID-19
patients ([Fig. 1C ]). Throughout this manuscript and unless the timing is specifically stated, outcomes
described for “hospitalized patients” refer to outcomes occurring at any time during
the follow-up period, both during the time that the patients were in-hospital and
following their discharge. No other exclusion criteria were applied to the dataset.
The index date was defined as the date of the earliest evidence of confirmed COVID-19
on or after January 21, 2020 ([Fig. 1 ]). Patients were also required to be aged 18 years or older as of the index date
and to have had activity in the Optum EHR COVID database at least 12 months prior
to the index date, which was defined as the baseline period. Patients with missing
data on sex or birth year were excluded from the study. The period from the index
date to the last activity date (up to January 7, 2021) in the database was considered
as the follow-up period, which included both the hospitalization period and the time
following discharge. Time of death was defined as the last day of the calendar month
during which the patient died.
Demographics, Medications of Interest, and Outcomes
Patient demographic and clinical characteristics: Demographics were assessed on the
index date and included age, sex, race, ethnicity, geographic region, insurance type,
and month and year of index date. Clinical characteristics were assessed during the
12-month baseline period and included BMI and obesity class based on the last measure
before the index date, comorbidities ([Supplemental Table S2 ]), Quan–Charlson comorbidity index (QCI) score[29 ] ([Supplemental Table S3 ]), and concomitant medication use ([Supplemental Table S4 ]).
Anticoagulant, anti-inflammatory/immunomodulatory, and thrombolytic medications: These
medications of interest included anticoagulants, antiplatelets, tissue plasminogen
activator, aspirin, antithrombin III, remdesivir, corticosteroids, and convalescent
plasma ([Supplemental Table S5 ]). The use of any of these treatments during the follow-up period was assessed in
total and by the medication type. Treatment users were defined as patients with the
use of any of the medications of interest during the follow-up period. Prior users
were defined as patients with the use of any medications of interest during the follow-up
period who also received any of the medications of interest within the 45 days prior
to the index date. The number and proportion of treatment users and prior users of
any medication in the class (overall and by each medication class) were assessed.
Occurrence of thromboembolic events and all-cause mortality: Thromboembolic events
included ATE, including ischemic stroke, myocardial infarction (MI), acute limb ischemia
and major nontraumatic lower limb amputation, and VTE, including deep vein thrombosis
(DVT) and pulmonary embolism (PE; [Supplemental Table S6 ]). The occurrence of thromboembolic events and time to the first event during the
follow-up period were assessed in total and by each event of interest. All-cause mortality
was determined as the number and proportion of patients who died during follow-up
and the time to death was estimated from the date of death, defined in the Optum EHR
COVID database as the last day of the calendar month during which the patient died.
Exploratory Outcomes. The following exploratory analyses were assessed:
The length of hospital stay.
Timing of thromboembolic event occurrence and medication use (during hospitalization
or after discharge).
The percentage of patients who received any of the medications of interest during
hospitalization or after discharge.
The percentage of patients who received any of the medications of interest within
45 days prior to the index date and who also received the same medication anytime
during the follow-up period.
The feasibility of incorporating COVID-19 risk stratification scores (i.e., the Northwell
COVID-19 Survival [NOCOS] calculator[30 ] and the International Medical Prevention Registry on VTE and D-dimer [IMPROVE-DD]
VTE Risk Score[31 ]
[32 ]) was assessed by evaluating the availability of the risk score components in the
database.
Subgroup Analysis. Among patients with a COVID-19 hospitalization, a subgroup analysis was performed
to assess the occurrence of thromboembolic events in patients who were admitted to
the ICU during the index hospitalization and those who were not admitted to the ICU.
Data Analysis
Descriptive analyses were conducted for all study cohorts using univariate statistics
including frequencies, percentages, means, standard deviations (SDs), medians, and
interquartile range (IQR). No formal statistical tests or comparative assessments
among patient groups or medications were performed in this study.
Results
Patient Demographic and Clinical Characteristics
A total of 1,246,067 patients who had one or more EHR encounter with a code for COVID-19
in any diagnosis position during the cohort identification period were identified.
After all eligibility criteria were applied, 181,995 patients were included in the
overall cohort of COVID-19 patients, with a mean (SD) age of 50.0 (18.7) years and
mean (SD) QCI score of 0.6 (1.4) ([Supplemental Table S7 ]). Of these COVID-19 patients, 40,524 (22.3%) were hospitalized ([Table 1 ]). During the period from January 2020 to January 2021, hospital admissions of these
COVID-19 patients were highest during November, December, and April of 2020 ([Fig. 2 ]). In the subset of patients with a COVID-related hospitalization, which is the focus
of this manuscript, the mean (SD) age was 63.4 (17.4) years and nearly 20% of patients
were African American ([Table 1 ]). Among the 62% of patients with a BMI measure available, mean (SD) BMI was 32.3
(8.7) kg/m2 . The mean (SD) QCI score was 1.3 (2.0) in hospitalized patients, with hypertension,
hyperlipidemia, and diabetes being the most common comorbidities. Prior ischemic stroke
and MI occurred in 3.0% of hospitalized patients, while prior DVT occurred in 1.9%
and prior PE occurred in 1.3% ([Table 1 ]). Baseline medication use was generally consistent with the presence of comorbidities
([Table 2 ]). The highest reported medication used over the 12 months prior to the index date
was antibiotics (34.6%), followed by antihypertensives (27.5%) and antihyperlipidemics
(27.2%). Anticoagulants were used in 22.4% of hospitalized patients during the baseline
period.
Table 1
Demographics and baseline[a ] clinical characteristics of hospitalized COVID-19 patients
Number of patients
40,524
Age, years
Mean (SD)
63.44 (17.36)
Age group, years, n (%)
18–24
869 (2.14)
25–34
2,322 (5.73)
35–44
3,067 (7.57)
45–54
5,067 (12.50)
55–64
8,208 (20.25)
65+
20,991 (51.80)
Sex, n (%)
Male
20,193 (49.83)
Female
20,331 (50.17)
Race, n (%)
African American
7,912 (19.52)
Asian
864 (2.13)
Caucasian
25,580 (63.12)
Other/unknown
6,168 (15.22)
Ethnicity, n (%)
Hispanic
5,167 (12.75)
Not Hispanic
31,918 (78.76)
Unknown
3,439 (8.49)
Geographic region, n (%)
Northeast
10,174 (25.11)
West
3,100 (7.65)
Midwest
15,945 (39.35)
South
10,004 (24.69)
Other/unknown
1,301 (3.21)
Insurance type, n (%)
Commercial
10,178 (25.12)
Medicaid
2,983 (7.36)
Medicare
9,326 (23.01)
Others
11,813 (29.15)
Uninsured
436 (1.08)
Unknown
1,355 (3.34)
Missing
4,433 (10.94)
BMI, kg/m2
Patients with BMI measure, n (%)
25,178 (62.13)
Mean BMI (SD)[b ]
32.27 (8.70)
BMI category, n (%)[b ]
Underweight
379 (1.51)
Normal
4,143 (16.45)
Overweight
6,737 (26.76)
Obese
13,919 (55.28)
Obesity class, n (%)[b ]
Class 1 (BMI 30.0–34.9 kg/m2 )
6,127 (24.33)
Class 2 (BMI 35.0–39.9 kg/m2 )
3,849 (15.29)
Class 3 (BMI ≥40 kg/m2 )
3,943 (15.66)
QCI, mean (SD)
1.28 (1.99)
Individual comorbidity, n (%)
Hypertension
18,525 (45.71)
Hyperlipidemia
14,197 (35.03)
Diabetes
10,716 (26.44)
Anemia
6,342 (15.65)
Chronic kidney disease
6,133 (15.13)
Osteoarthritis
5,393 (13.31)
Nonalcoholic fatty liver disease
5,272 (13.01)
Depression
4,874 (12.03)
Thyroid disease
4,811 (11.87)
Anxiety
4,799 (11.84)
Congestive heart failure
4,719 (11.64)
Chronic obstructive pulmonary disease
4,339 (10.71)
Sleep apnea
3,597 (8.88)
Asthma
3,209 (7.92)
Cancer[c ]
2,932 (7.24)
Prior stroke/transient ischemic attack
2,442 (6.03)
Peripheral vascular disease
1,785 (4.40)
Old MI
1,770 (4.37)
Osteoporosis
1,510 (3.73)
Rheumatoid arthritis
728 (1.80)
Liver cirrhosis
514 (1.27)
Stable angina
454 (1.12)
Unstable angina
212 (0.52)
Uveitis
39 (0.10)
Prior thromboembolic event, n (%)
Ischemic stroke
1,226 (3.03)
MI
1,195 (2.95)
DVT
761 (1.88)
PE
518 (1.28)
ALI
124 (0.31)
Major nontraumatic lower limb amputation
160 (0.39)
Abbreviations: ALI, acute limb ischemia; BMI, body mass index; COVID-19, coronavirus
2019; DVT, deep vein thrombosis; MI, myocardial infarction; PE, pulmonary embolism;
QCI, Quan–Charlson comorbidity index; SD, standard deviation.
a The baseline period was defined as the 12 months prior to the index date.
b Mean BMI, BMI categories, and obesity classes were identified among hospitalized
patients with a BMI measure available (n = 25,178).
c A diagnosis for cancer required two diagnosis codes for the same type of cancer at
least 30 days apart.
Fig. 2 Month of index COVID-19 diagnosis for all patients and hospitalized patients. COVID-19,
coronavirus 2019.
Table 2
Baseline medication use in hospitalized COVID-19 patients
Baseline medication use,[a ]
n (%)
Hospitalized patients (n = 40,524)
Antibiotics
14,007 (34.56)
Antihypertensives
11,159 (27.54)
Antihyperlipidemics
11,004 (27.15)
Beta-blockers
9,486 (23.41)
Anticoagulants
9,095 (22.44)
Corticosteroids
8,927 (22.03)
Antidiabetics
8,731 (21.55)
Diuretics
7,978 (19.69)
Anti-inflammatory agents
7,209 (17.79)
Antiplatelet agents
6,974 (17.21)
Calcium channel blockers
6,844 (16.89)
Antiarrhythmics
6,821 (16.83)
Antidepressants
6,813 (16.81)
Antianxiety agents
5,057 (12.48)
Antineoplastic agents
1,345 (3.32)
Abbreviation: COVID-19, coronavirus 2019.
a The baseline period was defined as the 12 months prior to the index date.
Results During Follow-Up
For all hospitalized patients, the overall mean (SD) time from index to end of follow-up
was 80.3 (82.8) days, with a median (IQR) of 43 (18–123) days.
Relevant Medication Use
Nearly all (94.8%) hospitalized patients used a medication of interest during follow-up
([Table 3 ]). Anticoagulants were used in 90.9% of hospitalized patients, with low molecular
weight heparins (LMWHs) being the most frequently used anticoagulant (70.2%). Among
hospitalized patients, 38.6% received antiplatelet agents, 63.7% received corticosteroids,
and 35.5% received remdesivir. Convalescent plasma was used in 8.4% of hospitalized
patients. Nearly, 20% of patients used an anticoagulant after discharge ([Table 4 ]).
Table 3
Use of medications of interest during follow-up in hospitalized COVID-19 patients
Medication use during follow-up
Both prior use[a ] and follow-up use[b ]
Number of patients
40,524
40,524
Medication use, n (%)
Any of the medications of interest[c ]
38,403 (94.77)
5,014 (12.37)
Anticoagulants
Any anticoagulants[d ]
36,824 (90.87)
2,773 (6.84)
Vitamin K antagonists
1,291 (3.19)
229 (0.57)
Factor Xa inhibitors
7,744 (19.11)
651 (1.61)
UFH
13,634 (33.64)
983 (2.43)
LMWH
28,458 (70.23)
778 (1.92)
DTIs
344 (0.85)
24 (0.06)
Antiplatelets[e ]
15,635 (38.58)
1,585 (3.91)
Aspirin
14,798 (36.52)
578 (1.43)
tPA
2,448 (6.04)
85 (0.21)
Remdesivir
14,403 (35.54)
26 (0.06)
Corticosteroids
25,809 (63.69)
2,083 (5.14)
Convalescent plasma
3,384 (8.35)
0
Antithrombin III
4 (0.01)
0
Abbreviations: COVID-19, coronavirus 2019; DTI, direct thrombin inhibitor; LMWH, low
molecular weight heparin; tPA, tissue plasminogen activator; UFH, unfractionated heparin.
a Prior use was defined as documentation of the medication(s) of interest during the
45-day period prior to the index date.
b Follow-up use was defined as documentation of the medication(s) of interest on or
after the index date.
c The medications of interest included anticoagulants, antiplatelets, aspirin, tPA,
remdesivir, corticosteroids, convalescent plasma, and antithrombin III.
d Anticoagulants included vitamin K antagonists, factor Xa inhibitors, UFH, LMWH, and
DTIs.
e Antiplatelet medications did not include aspirin.
Table 4
Thromboembolic events and mortality during follow-up in hospitalized COVID-19 patients
Number of patients
40,524
Occurrence of thromboembolic events, n (%)
Any of the thromboembolic events of interest[a ]
7,113 (17.55)
Ischemic stroke
1,544 (3.81)
MI
3,119 (7.70)
DVT
1,761 (4.35)
PE
1,849 (4.56)
ALI
89 (0.22)
Major nontraumatic lower limb amputation
118 (0.29)
Time to first event (days),[b ] mean (SD)
Any of the thromboembolic events of interest[a ]
15.0 (34.2)
Ischemic stroke
23.7 (47.1)
MI
12.3 (31.3)
DVT
22.3 (41.2)
PE
14.6 (30.1)
ALI
38.8 (57.9)
Major nontraumatic lower limb amputation
33.6 (56.0)
Death[c ]
Patients who died during follow-up, n (%)
6,077 (15.0)
Time to death (days), mean (SD)
39.0 (32.2)
Abbreviations: ALI, acute limb ischemia; COVID-19, coronavirus 2019; DVT, deep vein
thrombosis; MI, myocardial infarction; PE, pulmonary embolism; SD, standard deviation.
a The thromboembolic events of interest included ischemic stroke, MI, DVT, PE, ALI,
and major nontraumatic lower limb amputation.
b Time to first event was examined among patients with the event.
c In the Optum COVID-19 dataset, the death date was defined as the last day of the
calendar month during which the patient died. Therefore, the results reported here
are an estimate.
Thromboembolic Events and Mortality
Among patients with a COVID-19 hospitalization, thromboembolic events of interest
occurred in 7,113 patients (17.6%; [Table 5 ]), with 13.4% experiencing an event during hospitalization and 4.3% experiencing
an event only after hospital discharge ([Table 4 ]). Time to first thromboembolic event is shown in [Fig. 3 ]. During hospitalization, MI was the most common thromboembolic event, followed by
PE, DVT, and ischemic stroke. After discharge, the proportions of patients with MI,
DVT, PE, and ischemic stroke were similar.
Table 5
Exploratory analysis: thromboembolic events and medication use during hospitalization
and after discharge (not mutually exclusive)
During hospitalization
After discharge (includes patients who had a thromboembolic event only after discharge
from index hospitalization)
Total number of patients[a ]
40,524
37,541
Occurrence of thromboembolic events, n (%)
Any of the thromboembolic events of interest[b ]
5,430 (13.40)
1,603 (4.27)
Ischemic stroke
1,080 (2.67)
443 (1.18)
MI
2,497 (6.16)
574 (1.53)
DVT
1,205 (2.97)
542 (1.44)
PE
1,372 (3.39)
465 (1.24)
ALI
47 (0.12)
39 (0.10)
Major nontraumatic lower limb amputation
86 (0.21)
32 (0.09)
Time to first event (days), mean (SD)[c ]
Any of the thromboembolic events of interest[b ]
3.9 (5.7)
53.4 (56.4)
Ischemic stroke
4.4 (7.3)
71.6 (66.3)
MI
3.2 (5.2)
52.6 (56.6)
DVT
5.8 (8.5)
59.7 (57.8)
PE
4.6 (6.3)
44.5 (47.8)
ALI
3.6 (6.0)
83.5 (63.8)
Major nontraumatic lower limb amputation
6.6 (7.1)
105.9 (65.4)
Medication use, n (%)
Any of the medications of interest[d ]
37,917 (93.57)
9,582 (25.52)
Anticoagulants
Any anticoagulants[e ]
36,146 (89.20)
7,035 (18.74)
Vitamin K antagonist
1,143 (2.82)
475 (1.27)
Factor Xa inhibitor
6,939 (17.12)
2,425 (6.46)
UFH
12,213 (30.14)
2,853 (7.60)
LMWH
27,385 (67.58)
3,388 (9.02)
DTIs
286 (0.71)
77 (0.21)
Antiplatelets[f ]
14,490 (35.76)
3,612 (9.62)
Aspirin
13,666 (33.72)
3,269 (8.71)
tPA
2,065 (5.10)
483 (1.29)
Remdesivir
13,772 (33.98)
763 (2.03)
Corticosteroids
23,992 (59.20)
4,659 (12.41)
Convalescent plasma
3,302 (8.15)
29 (0.08)
Antithrombin III
2 (0.00)
2 (0.01)
Abbreviations: ALI, acute limb ischemia; DTI, direct thrombin inhibitor; DVT, deep
vein thrombosis; LMWH, low molecular weight heparin; MI, myocardial infarction; PE,
pulmonary embolism; SD, standard deviation; UFH, unfractionated heparin; tPA, tissue
plasminogen activator.
a Patients who died or were censored during hospitalization were excluded from the
total number of patients after discharge.
b The thromboembolic events of interest included ischemic stroke, MI, DVT, PE, ALI,
and major nontraumatic lower limb amputation.
c Time to first event was examined among patients with the event.
d The medications of interest included anticoagulants, antiplatelets, aspirin, tPA,
remdesivir, corticosteroids, convalescent plasma, and antithrombin III.
e Anticoagulants included vitamin K antagonists, factor Xa inhibitors, UFH, LMWH, and
DTIs.
f Antiplatelet medications did not include aspirin.
Fig. 3 Time to first thromboembolic event. The median (interquartile range) for thromboembolic
events to accrue was 4 (1, 17) days, and the probability of having the first thromboembolic
event at day 9 (mean duration of hospital stay) was 35.9%. SD, standard deviation.
The mean (SD) time from COVID-19 diagnosis to thromboembolic events for all hospitalized
patients was 15.0 (34.2) days, and the mean (SD) length of hospital stay was 9.2 (9.1)
days. For patients with an event during hospitalization, the mean (SD) time to thromboembolic
event was 3.9 (5.7) days, with the shortest time to MI (3.2 [5.2] days) and longest
times to DVT (5.8 [8.5] days) and major nontraumatic lower limb amputation (6.6 [7.1]
days). Of patients who were discharged, the mean (SD) follow-up period was 70.7 (82.0)
days after discharge. For patients who had a thromboembolic event only after discharge
from the hospital, the mean (SD) time to first event was 53.4 (56.4) days after COVID-19
diagnosis and ranged from 44.5 (47.8) days for PE to 105.9 (65.4) days for major nontraumatic
lower limb amputation. The mean (SD) time from discharge to event was 43 (56) days.
Death occurred in 6,077 (15.0%) of hospitalized COVID-19 patients ([Table 5 ]). The estimated mean (SD) time to death was 39.0 (32.2) days for all hospitalized
patients.
Risk Stratification Scores
In the exploratory analysis to determine the feasibility of assessing risk stratification
scores, a high proportion of hospitalized patients (>95%) had values available for
each of the elements of the NOCOS calculator, except for serum sodium levels, which
were available in 65.8% of the patients ([Supplemental Table S8 ]). After excluding patients with data not meeting the requirement for the NOCOS calculator,[30 ] the complete data of 22,557 (55.7%) hospitalized COVID-19 patients were entered
into the NOCOS calculator to assess their survival probability. These patients had
a mean 62.8% probability of survival. The IMPROVE-DD VTE risk score was calculated
for all hospitalized patients. If a component of IMPROVE-DD VTE risk score was not
found during index hospitalization, a value of 0 was assigned. Among all hospitalized
patients, the mean (SD) IMPROVE-DD VTE risk score was 3.0 (2.0). About three-quarters
of the hospitalized patients had IMPROVE-DD VTE risk score ≥2 (n = 30,060).
Subgroup Analysis
An ICU stay was recorded for 21.3% of hospitalized patients, of which 24.1% (n = 2,083) had a thromboembolic event of interest ([Supplemental Table S9 ]). The time to first thromboembolic event ranged from 9 days for MI to more than
1 month for major nontraumatic lower limb amputation in hospitalized patients admitted
to the ICU.
Discussion
Using a large EHR database of patients in the United States, we identified a cohort
of COVID-19 patients and assessed patient characteristics, relevant medication use,
and the occurrence of thromboembolic events and all-cause mortality. There are three
important findings from our work. First, nearly one-quarter of all identified COVID-19
patients were hospitalized, providing a cohort of more than 40,000 patients with a
COVID-19 hospitalization, which is substantially larger than previously reported real-world
analyses.[33 ]
[34 ] These patients had risk factors for more severe COVID-19, including older age, African-American
race, and a high QCI, which is indicative of comorbidity burden.[11 ]
[13 ] Although prior thromboembolic events were infrequently reported, 22.4% of hospitalized
patients had received anticoagulants during the 12-month baseline period prior to
their COVID-19 diagnosis. Second, thromboembolic events and all-cause mortality occurred
in 17.6 and 15.0% of hospitalized patients, respectively. Thromboembolic events occurred
in 13.4% of patients during hospitalization and were numerically higher among patients
in the ICU (24.1%) than those who did not have an ICU stay (15.8%). The rate of thromboembolism
was consistent with the rates of ATE and VTE reported in recent studies.[2 ]
[16 ] Third, the rate of postdischarge thromboembolic events of 4.3% was higher than previously
reported among smaller cohorts[35 ]
[36 ]
[37 ]
[38 ] but similar to the larger CORE-19 registry.[34 ]
This observational and descriptive study utilized a geographically diverse database
spanning all 50 states to provide results that are generalizable to all COVID-19 patients
across the United States. In addition, this database has a lag time of only 1 to 2
months, allowing near real-time analysis of real-world data. COVID-19 patients were
identified using nonantibody tests, which have very high specificity and limited false-positive
results.
A cohort study of 1,351 hospitalized COVID-19 patients in Michigan provides consistent
results to ours for mortality while examining the use of prophylactic versus treatment-dose
anticoagulants.[33 ] Overall, anticoagulation was administered to 88% of patients, with more intensive
therapy to older patients, those with longer hospital stays, more comorbidities, and
more severe disease. Prophylactic VTE treatment was reported for 83.4% of patients,
while 16.2% received treatment-dose anticoagulation. The rate of confirmed VTE was
1.3% after day 2 of hospitalization. The in-hospital mortality rate was 15.8% for
patients who received prophylactic anticoagulants and 33.8% for those who received
treatment-dose anticoagulants, but both methods of anticoagulation were associated
with lower in-hospital mortality compared with no anticoagulation.[33 ] In another study using a multihospital integrated health care network in New York,
a retrospective cohort study identified 9,407 hospitalized COVID-19 patients.[5 ] Most patients were aged older than 60 years (63.8%), male (59.3%), and had hypertension
(59.9%), along with other comorbidities. During hospitalization, 18.6% of patients
received treatment-dose thromboprophylaxis and 71.0% received prophylactic dose, while
10.4% received no initial hospital thromboprophylaxis. VTE occurred in 2.9% of patients,
with a higher rate in the ICU versus medical ward (4.9 vs. 2.4%). Of those who developed
at least 1 VTE, 10.2% did not receive anticoagulation prior to diagnosis, 65.7% received
prophylactic dose, and 24.1% received treatment dose. The overall VTE or mortality
rate was 26.1% and followed similar trends as the VTE rate for patient sex, hospital
location, and D-dimer levels. VTE or mortality increased with increasing comorbidity
burden. These results provide support for in-hospital thromboprophylaxis.[5 ] Given the high rate of thromboembolic events, current guidelines from health organizations
and hematologic societies suggest the use of prophylactic anticoagulants, with LMWH
as drug of choice, for hospitalized COVID-19 patients.[6 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[24 ] Our analysis indicates that these guidelines are being followed, with 95% of hospitalized
patients receiving anticoagulants and LMWH used in 70% of patients. Recent randomized
trials suggest advantages of therapeutic-dose thromboprophylaxis over standard thromboprophylaxis
in medical ward COVID-19 inpatients, especially those with elevated D-dimer levels.[25 ]
[26 ]
[28 ] This advantage was not seen in critically ill COVID-19 in-patients.[26 ]
[27 ]
The effect of COVID-19 on postdischarge thromboembolism, and associated continued
use of thromboprophylaxis, is less clear.[39 ] Our study found a posthospital discharge rate of thromboembolism of 4.3%. This rate
is similar to the largest prospective study of postdischarge rates of thromboembolism
and mortality in over 4,900 hospitalized COVID-19 patients in the CORE-19 registry.[34 ] During hospitalization, thromboprophylaxis was reported for 82.3% of patients, while
postdischarge thromboprophylaxis was reported for 12.7% of patients, with a rate of
21.5% postdischarge thromboprophylaxis for patients with an IMPROVE-DD VTE risk score
≥4. Postdischarge VTE and ATE occurred in 1.6 and 1.7% of patients, respectively,
and postdischarge all-cause mortality was 4.8%. Key predictors of postdischarge thromboembolic
events in the CORE-19 registry were advanced age (>75 years), cardiovascular risk
factors, chronic kidney disease, IMPROVE-DD VTE score ≥4, and an ICU stay. The risk
of major thromboembolic events and death was reduced by 46% in patients who received
postdischarge anticoagulants.[34 ] The Northwell Health System policy advocated for the extended use of thromboprophylaxis
for 30 days after hospitalization based on randomized trials in high-risk medically
ill patients.[40 ]
[41 ] In our study, 4.3% of patients developed thromboembolic events only after discharge
despite anticoagulant use in 18.7% of patients, although it is not known if the events
occurred in patients receiving anticoagulants. The recently published MICHELLE trial
using both the IMPROVE-DD VTE tool with a score of 4 or more or a score of 2 to 3
and elevated D-dimer to select high-risk COVID-19 inpatients in the postdischarge
period revealed a 6% absolute risk reduction (67% relative risk reduction; relative
risk 0.33; 95% CI: 0.12–0.90; p = 0.0293) of major thromboembolic events and cardiovascular death favoring postdischarge
extended thromboprophylaxis with rivaroxaban over no anticoagulation.[42 ]
Risk stratification tools are helpful in managing the influx of pandemic patients
by identifying more severely ill patients and advising therapeutic decisions. We assessed
the feasibility of determining the NOCOS calculator and IMPROVE-DD VTE risk score
based on the presence of score characteristics in our database population. Both risk
assessment models have been validated in hospitalized COVID-19 patients.[30 ]
[31 ]
[32 ] Most patients (>95%) had some data available for the components of the NOCOS calculator;
however, only 55.7% had complete NOCOS data. Using these data, their mean survival
probability was 62.8%, which indicates a seriously ill population but also overestimates
the observed mortality rate of 15%, suggesting that the NOCOS calculator was not feasible
for use in this population. Fewer patients (0.3–74.4%) had data available for components
of the IMPROVE-DD VTE risk score. Using a value of 0 for missing data, which may underestimate
VTE risk, results of the IMPROVE-DD VTE score for all hospitalized COVID-19 patients
suggested an overall moderate-to-high risk of VTE.
Inherent to claims analyses, data coding is not without its limitations. Given the
observational and descriptive study design, causal inferences between treatment and
outcomes were not assessed. Some limitations of the data sources include the fact
that health care provider organizations must participate in the EHR network to be
included so that data on the geographic distribution of the cohort may be impacted
by geographic differences in network participation. Second, patients may receive laboratory
tests based on their risk for certain conditions, and thus, these patients may have
different demographic and clinical characteristics than patients who do not receive
such tests. As atrial fibrillation is known to occur in COVID-19 patients, the lack
of data on this condition may have impacted the outcomes. Third, death data were not
available for all patients. The dataset used in this study also included a very small
proportion of uninsured patients. We also note that the study was conducted using
data from 2020 and represents COVID-19 at that time. The effect of differences in
viral variants, COVID-19 patient populations, and treatments over time on thromboembolic
events was also not determined.[43 ]
[44 ] In addition, we could not determine if death occurred during hospitalization or
after discharge due to limitations around death date in the dataset. Because the death
date was defined as the last day of the calendar month during which the patient died,
time of death in this study is an estimation. Further, this analysis examined the
number of patients with various thromboembolic events but did not count multiple occurrences
of the same event for each patient. It is possible that events competed with each
other and death in this cohort (as subclinical thrombotic disease) was found in 60%
of COVID-19 patient autopsies.[45 ] Written prescriptions captured in EHR data do not necessarily indicate that the
medication was taken. The use of aspirin, an over-the-counter medication in the United
States, may also have been underestimated. Differences in patient characteristics
and treatment objectives associated with each of the treatments of interest may limit
interpretability of the results of this study.
Although this study is based on a population of patients that was earlier in the pandemic
and may thus have been qualitatively different than patient populations at this time,
the fundamental risk conditions for risk stratification and poor outcomes of hospitalized
patients are strongly supported by this study. Particularly given the overall mortality
rate of this population, results from our study demonstrate the value of leveraging
large real-world datasets to characterize the thromboembolic complications of COVID-19,
both during hospitalization and particularly in the posthospitalization period. Further
high-quality studies exploring the relationship of baseline thromboprophylaxis with
the incidence of COVID-19–related in-hospital VTE and posthospitalization VTE and
death will be needed to establish the evidence base for informing the use of extended
thromboprophylaxis following COVID-19 hospitalization.
Conclusions
In a cohort of more than 40,000 hospitalized COVID-19 patients, thromboembolic events
occurred in 18% and the mortality rate was 15%. Importantly, 4% of thromboembolic
events developed only after discharge from the hospital. These findings support further
study of the effects of COVID-19 on coagulopathy and optimization of thromboprophylaxis
for patients hospitalized for COVID-19, both during hospitalization and in the immediate
postdischarge period.
What is known on this Topic?
Thromboembolism is a substantial concern for hospitalized patients with COVID-19,
and the effect appears to extend into the postdischarge period.
Most treatment guidelines recommend prophylactic anticoagulation for hospitalized
COVID-19 patients to lower the risk of thromboembolism and mortality.
This study evaluated patient characteristics, medication use, thromboembolic events,
and all-cause mortality in a large, observational cohort of more than 40,000 patients
hospitalized with COVID-19 in the United States.
What does this Paper Add?
In this study, 13.4% of patients experienced a thromboembolic event during hospitalization
and 4.3% experienced a thromboembolic event only after discharge; 15% of patients
died during follow-up.
Among hospitalized COVID-19 patients, those who experienced a thromboembolic event
were characterized by trends toward older age and increased comorbidity burden.
The size and geographic distribution of this analysis are sufficiently robust as to
describe what may be considered as the current standard of care in the management
of patients suffering from COVID-19 and may be particularly relevant when institutions
and professional societies consider the construction of guidelines and care pathways
for this patient population.
