924 Review Article

Prevention of Venous Thromboembolism in Hospitalized

Medically Ill Patients: A U.S. Perspective
Alex C. Spyropoulos1 Walter Ageno2 Alexander T. Cohen3 C. Michael Gibson4
Samuel Z. Goldhaber5 Gary Raskob6

1 Department of Medicine, Anticoagulation and Clinical Thrombosis Address for correspondence Alex C. Spyropoulos, MD, Department of
Services, Zucker School of Medicine at Hofstra/Northwell, The Medicine, Anticoagulation and Clinical Thrombosis Services, Zucker
Feinstein Institute for Medical Research, Northwell Health at Lenox School of Medicine at Hofstra/Northwell, The Feinstein Institute for
Hill Hospital, New York, New York, United States Medical Research, Northwell Health at Lenox Hill Hospital, 130 E 77th
2 Department of Medicine and Surgery, University of Insubria, Varese, Italy Street, New York, NY 10075, United States
3 Department of Haematological Medicine, Guy’s and St Thomas’ NHS (e-mail: aspyropoul@northwell.edu).
Foundation Trust, King’s College London, London, United Kingdom
4 Baim Institute, Boston, Massachusetts, United States
5 Division of Cardiovascular Medicine, Brigham and Woman’s Hospital,
Harvard Medical School, Boston, Massachusetts, United States
6 University of Oklahoma Health Sciences Center, Hudson College of
Public Health, Oklahoma City, Oklahoma, United States

Thromb Haemost 2020;120:924–936.

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Abstract Venous thromboembolism (VTE) remains a major cause of morbidity and mortality in
hospitalized medically ill patients. These patients constitute a heterogeneous popula-
tion, whose VTE risk is dependent upon the acute medical illness, immobility status,
and patient-specific risk factors that have been incorporated into individualized VTE risk
assessment models. Randomized placebo-controlled trials (RCTs) have shown both
efficacy and net clinical benefit of in-hospital thromboprophylaxis, which is supported
by guideline recommendations. The data for extended posthospital discharge throm-
boprophylaxis are more nuanced. RCTs comparing standardized duration low-molecu-
lar weight heparin versus extended duration direct oral anticoagulants, such as
betrixaban and rivaroxaban, have shown efficacy and net clinical benefit in select
groups of high VTE and low-bleed risk populations of hospitalized medically ill patients.
These oral agents are now approved for both in-hospital and extended thrombopro-
phylaxis. However, the most recent guidelines do not recommend routine use of these
agents for extended thromboprophylaxis. Longitudinal studies in medically ill patients
Keywords have shown that the majority of VTE events occur in the posthospital discharge setting
► venous within 6 weeks of hospitalization. This, coupled with the short hospital length-of-stay
thromboembolism and lack of routine postdischarge thromboprophylaxis in U.S. health care settings, has
► medically ill dampened quality improvement efforts aimed at reducing hospital-acquired VTE. The
► extended aim of this multidisciplinary document is to provide an evidence-based framework to
thromboprophylaxis guide clinicians in assessing VTE and bleeding risk in hospitalized medically ill patients
► heparin using an individualized, risk-adapted, and patient-centered approach, with the aim of
► direct oral providing clinical pathways toward the use of appropriate type and duration of
anticoagulants available thromboprophylactic agents.

received © 2020 Georg Thieme Verlag KG DOI https://doi.org/

December 19, 2019 Stuttgart · New York 10.1055/s-0040-1710326.
accepted after revision ISSN 0340-6245.
April 3, 2020
 Venous Thromboprophylaxis in Medically Ill Patients
Introduction
Venous thromboembolism (VTE), comprising of deep vein
thrombosis (DVT) and pulmonary embolism (PE), continues
to be a major cause of morbidity and mortality in hospital-
ized medically ill patients. It is estimated that in the U.S.
alone, approximately 50% of the 7.2 million medically ill
patients that are hospitalized every year are at risk of VTE,
while approximately 25% or more at high risk of VTE in the
posthospital discharge period.1,2 Hospitalization for medical
illness accounts for more than one-quarter of the incident
VTE events that occur within 90 days of hospitalization in the
community.3 The economic impacts of VTE in this population
in the U.S. are substantial, with estimates ranging from 7 to
10 billion U.S. dollars for the incremental costs of incident
VTE, and annualized total health care costs estimated at
more than 39 billion U.S. dollars when the costs of all VTE
events and long-term sequelae are included.4,5
Medically ill patients are older, have more comorbidities,
and have more underlying chronic cardiopulmonary disease
compared with surgical patients and as such have more severe
forms of VTE, including more proximal DVT, and importantly,
more VTE-related death.6,7 More than 75% of hospital-based
fatal PEs occur in nonsurgical medically ill patients.8 The
immediate hospital postdischarge period remains an especially
high VTE risk period in medically ill patients.9
The rationale for thromboprophylaxis in hospitalized med-
ically ill patients is based on both the high incidence of VTE and
its clinically silent nature in this population, in which the initial
presentation may be sudden death in up to 7.6% of patients.10
The results of older inpatient-based randomized placebo-con-
trolled trials with unfractionated heparin (UFH), low-molecu-
lar-weight heparin (LMWH), or pentasaccharide fondaparinux
have shown a 50 to 60% reduction of total VTE that included
both symptomatic VTE and asymptomatic lower extremity
DVT (established by screening venography or ultrasonography)
that firmly established the effectiveness and net clinical benefit
of short term use of thromboprophylaxis given for a duration of
6 to 14 days.11–13 This recommendation has been supported by
antithrombotic guidelines.14 However, the shortened hospital
length-of-stay in the U.S., which now averages 4.5 days, coupled
with fewer than 4% of hospitalized medically ill patients in
the U.S. receiving postdischarge thromboprophylaxis, has
dampened the treatment effects of in-hospital thrombopro-
phylaxs.15,16 Recent data suggests that approximately half of all
VTE events occur after discharge in this population.9,17
Data supporting extended thromboprophylaxis in hospi-
talized medically ill patients are nuanced. Approximately 25
to 40% of U.S. medically ill patients are at sufficient VTE risk
to benefit from extended thromboprophylaxis.2,18 Although
the initial randomized placebo-controlled trials with the
LMWH enoxaparin and direct oral anticoagulants (DOACs)
rivaroxaban and apixaban failed to establish a definitive net
clinical benefit in support of those agents, more recent
evidence from a large randomized trial with the DOAC
betrixaban in high VTE risk groups as well as safety and
net clinical benefit of rivaroxaban in a recent large random-
ized trial and in a large patient subgroup of an earlier
Spyropoulos et al. 925
randomized trial that excluded key bleeding risk factors
have led to regulatory approval of both betrixaban and
rivaroxaban for extended thromboprophylaxis in medically
ill patients.19–21 In contrast, antithrombotic guidelines have
recommended an individualized approach to extended
thromboprophylaxis or recommended against routine use
of extended thromboprophylaxis with DOACs in medically ill
patients.22,23
Multinational audits have consistently shown underutili-
zation of in-hospital guideline-recommended thrombopro-
phylaxis in medically ill patients, mainly due to a perception
of lower VTE risk and higher bleed risk than that reported in
clinical trials.24 Population-based studies in the U.S. suggest
that the use of a “universal” in-hospital-based thrombopro-
phylactic strategy does not reduce the community burden of
VTE from medically ill patients.15,16 Recent antithrombotic
guidelines have adopted the use of an individualized approach
in assessing a patient’s VTE and bleed risk, of which two VTE
risk models—Padua and IMPROVE VTE—and one bleed risk
model—IMPROVE Bleed—have gained acceptance after exten-
sive external validation.14,23
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This multidisciplinary document will review the most cur-
rent concepts of predicting and preventing VTE in medically ill
patients, and discuss emerging paradigms of thromboprophy-
laxis in this population, especially from a U.S. health system
perspective. We will provide an evidence-based framework to
guide clinicians in assessing VTE and bleeding risk in hospital-
ized medically ill patients using an individualized, risk-adapted,
and patient-centered approach, with the aim of providing
clinical pathways toward the use of appropriate type and
duration of available thromboprophylactic agents.
Acute Medical Illnesses, Immobility, and VTE Risk
Patients hospitalized for an acute medical illness are a
heterogeneous group. However, factors related to a specific
underlying illness or acute exacerbation of a chronic under-
lying cardiopulmonary condition, especially if it is associated
with immobility, would predispose a patient to a greater risk
of VTE. Thus, medically ill patients with relative immobility
and hospitalized with congestive heart failure (CHF), respi-
ratory insufficiency, stroke, or those admitted to the medical
intensive care unit (ICU) all have an increased risk for VTE,
with rates reported from 10 to 75% in the absence of
thromboprophylaxis using objective testing.25 Acute infec-
tious disease is also an independent risk factor for VTE, with
odds ratios (ORs) varying from 1.74 to 1.94.26,27 Patients
with autoimmune or rheumatic disease, especially inflam-
matory bowel disease, psoriasis, and rheumatoid arthritis,
also are at increased risk of VTE.28 Finally, malignancy, either
in the acute stage or within 5 years of presentation, also
presents an increased risk for VTE.29
Immobility is an independent risk factor for VTE in medi-
cally ill patients, with results from a meta-analysis revealing an
OR of 2.52 (95% confidence interval [CI], 1.70–3.74).30 There
have been various definitions of immobility across thrombo-
prophylactic trials of medically ill that have either focused on
duration or nature of immobility.31 These have included
periods of time confined to bed, inability to attain autonomous
Thrombosis and Haemostasis Vol. 120 No. 6/2020
926 Venous Thromboprophylaxis in Medically Ill Patients Spyropoulos et al.

walking greater than 10 m, and total bed rest with and without Table 1 Risk factors for VTE in hospitalized patients14,26,78–80
bathroom privileges.31 More recent models have included
more pragmatic definitions of immobility that are tied to a Disease-specific
disease state and initial duration of hospitalization.32 • Heparin-induced
thrombocytopenia
Risk Factors for VTE in Medically Ill • Nephrotic syndrome
• Paraproteinemia
Both disease-specific and patient-specific risk factors for VTE,
• Behcet’s disease
along with a degree of immobility based on disease severity of • Nephrotic syndrome
an acute medical illness, contribute to an individual patient’s • Acute Infection/sepsis
overall VTE risk. However, these individual VTE risk factors are • Malignancy
not weighted equally. Patient-specific risk factors include • Polycythemia
• Paroxysmal nocturnal
advanced age, prior history of VTE, known thrombophilic
hemoglobinuria
conditions, prior history of cancer, and lower extremity paresis • Myeloproliferative
and have consistently been associated with an increased risk of disorders
VTE in this population,33 while others such as chronic venous • Congestive heart
insufficiency, obesity, varicose veins, and use of estrogen- failure
• Stroke
containing or erythropoietin-containing medications have
• Myocardial infarction
shown fewer consistent associations with VTE risk.33 A group • Prolonged immobility
of VTE risk factors collectively called the “APEX criteria” has • Pregnancy or
included Age
75 years, a Past history of cancer or VTE, and postpartum
EXtra risk factors (comorbidities that are risk factors for VTE) • Acute or chronic
Patient-specific
• High-dose oral estrogen
therapy
• Obesity (BMI > 35 kg/m2)
• History of DVT or PEa
• Family history of thrombosisb
• Sickle cell disease
• Age > 75 ya
• Varicose veins or venous
insufficiency
• History of malignancy
(within 5 y)
• Congenital or acquired
thrombophilia or
hypercoagulable state
(antithrombin deficiency,
protein C or S deficiency,
antiphospholipid antibodies,
factor V Leiden, or
prothrombin gene mutation)a

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lung disease
has also been proposed.18 Recently, a novel biomarker, an
• Acute inflammatory
elevated D-dimer (Dd)
2  upper limit of normal has also disease
shown promise in identifying high VTE risk in medically ill • Inflammatory
populations.34 A table of proposed key VTE risk factors is bowel disease
included (►Table 1). • Shock
• ICU/CCU stay
There are multiple VTE risk assessment models (RAMs)
based on individual risk factors for VTE in medically ill Biomarker
patients.35 Of these, the 11-factor Padua VTE RAM (which • Elevated D-dimer
was an extension of the previous Kucher VTE RAM) and the (> 2 ULN)
7-factor IMPROVE VTE RAM are based on weighted and scored
Abbreviations: BMI, body mass index; CCU, critical care unit; DVT, deep
instruments that have undergone extensive external validation vein thrombosis; ICU, intensive care unit; PE, pulmonary embolism; VTE,
and have been highlighted by recent guidelines23 (►Tables 2 venous thromboembolism.
a
and 3). The Padua VTE RAM uses a point system from 1 to 3 Key VTE risk factors (including APEX criteria).
b
points, designating a score of
4 points as high VTE risk, while Only first degree relative.

the IMPROVE VTE RAM uses a point system from 1 to 3 points,

designating a score of 2 to 3 as at VTE risk and a score of
4
points as high VTE risk.36 In large external validation studies,
Table 2 The Padua VTE RAMa,68
both VTE RAMs using model cutoffs identified patient groups at
three- to fourfold relative increased risk of VTE compared with Risk factor Points
nonhigh risk patients.37,38 The Padua VTE RAM has shown
Reduced mobility 3
moderate discrimination, while the IMPROVE VTE RAM has
shown moderate-to-good discrimination.36,37 More recently, Active cancer 3
an elevated Dd has been added to derive the IMPROVEDD VTE Prior venous thromboembolism 3
score which improves model discrimination.39 The Centers for (excludes superficial thrombophlebitis)
Medicaid and Medicare Services effective January 1, 2017 have Already known thrombophilic condition 3
mandated the use of either the Padua or IMPROVE VTE RAMs to Recent (< 1 mo) trauma and/or surgery 2
document VTE risk as part of the core measure of hospital-
Elderly age (> 70 y) 1
acquired preventable VTE in medically ill.40
Heart and/or respiratory failure 1
Risk Factors for Bleeding in Medically Ill Acute myocardial infarction or ischemic stroke 1
Several risk factors consistently predict high bleeding risk Ongoing hormonal treatment 1
(especially with the use of pharmacologic thromboprophylaxis)
Obesity (BMI > 30) 1
in medically ill patients.41 These include advanced age, a history
of thrombocytopenia, the presence of a gastroduodenal ulcer, Acute infection and/or rheumatologic disorder 1
and the presence of blood dyscrasias.41 Key exclusionary criteria Abbreviations: BMI, body mass index; RAM, risk assessment model; VTE,
from randomized trials included bleeding risk factors such as venous thromboembolism.
a
severe renal insufficiency (creatinine clearance < 30 mL/min), A score of 4 or more constitutes at-VTE risk.

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 Venous Thromboprophylaxis in Medically Ill Patients Spyropoulos et al. 927

Table 3 Risk score points assigned to each independent VTE risk Table 5 Clinically important bleeding risk score in medically ill:
factor in hospitalized acutely ill medical patients—the modified points assigned to each independent factor—the IMPROVE
IMPROVE VTE RAMa,32 bleed scorea,39

VTE risk factor Points for the risk score Bleeding risk factors Points
2
Previous VTE 3 Renal failure GFR 30–59 vs.
60 mL/min/m 1
Known thrombophiliab 2 Male vs. female 1
Current lower limb 2 Age 40–80 vs. < 40 y 1.5
paralysis or paresisc
Current cancer 2
History of cancerd 2
Rheumatic disease 2
Immobilizatione 1
CV catheter 2
ICU/CCU stay 1
ICU/CCU 2.5
Age
60 y 1
Renal failure GFR < 30 vs.
60 mL/min/m2 2.5
Abbreviations: CCU, critical care unit; ICU, intensive care unit; RAM, risk Hepatic failure (INR > 1.5) 2.5
assessment model; VTE, venous thromboembolism.
a
A score of 0–1 constitutes low VTE risk. A score of 2–3 constitutes Age
85 vs. < 40 y 3.5
9
moderate VTE risk. A score of 4 or more constitutes high VTE risk. Platelets < 50  10 cells/L 4
b
A congenital or acquired condition leading to an excess risk of thrombosis.
c
Leg falls to bed by 5 seconds, but has some effort against gravity
Bleeding in 3 mo before admission 4
(adapted from NIH stroke scale). Active gastroduodenal ulcer 4.5

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d
Cancer (excluding nonmelanoma skin cancer) present at any time in the
past 5 years (cancer must be in remission to meet eligibility criteria).
e
Strict definition is complete immobilization confined to bed or
chair
7 days; modified definition is complete immobilization con-
fined to bed or chair
1 day with or without bathroom privileges.
Abbreviations: CCU, critical care unit; CV, central venous; GFR, glo-
merular filtration rate; ICU, intensive care unit; INR, international
normalized ratio.
a
A score of 7 or more constitutes high bleed risk.

severe liver disorders, the presence of human immunodeficien- cohort at high risk of major bleeding (MB) (MB risk at 14 days
cy virus, and uncontrolled hypertension.19,20 Recent analysis of 4.1% vs. 0.4%).42 Subsequent external validation studies of
from the MAGELLAN trial of extended thromboprophylaxis of this RAM support the notion that approximately 10 to 20% of
medically ill patients with rivaroxaban identified five key medically ill patients are at high bleed risk with pharmaco-
bleeding risk factors that categorized approximately 20% of logic thromboprophylaxis.43
the study population at high bleed risk.21 These included active
cancer, the presence of dual antiplatelet therapy, a recent bleed
Periods of VTE Risk in Hospitalized Medically
within 3 months, bronchiectasis or pulmonary cavitation, or
Ill Patients and Thromboprophylactic
bleeding within 3 months of index hospitalization.21 A table of
Strategies
bleeding risk factors is included (►Table 4).
The only evidence-derived and validated bleed risk model The risk of VTE in hospitalized medically ill patients can be
in medically ill patients remains the IMPROVE Bleed RAM42 conceptualized into two periods surrounding an index hos-
(►Table 5). This RAM uses 13 clinical and laboratory varia- pitalization as shown in ►Fig. 1.36
bles that are scored, with a score of
7 identifying a patient
1. The acute hospitalization period (up to 14 days), where VTE
risk is tied to immobility and disease severity, such as
Table 4 Risk factors for clinically important bleeding in acute exacerbations of chronic cardiopulmonary diseases,
hospitalized medical patients as well as intrinsic patient risk factors for VTE.
2. The immediate post hospital discharge period (30 days up
Disease-specific Patient-specific
to 45 days), where VTE risk continues to rise exponentially
• History of pulmonary • Severe renal insufficiency until it plateaus at approximately 45 days or so posthos-
cavitation/bronchiectasisa (CrCL < 30 mL/min)a pital discharge.
• Recent history of bleed • Severe thrombocytopenia
(within 3 mo)a (platelet counts Regarding the acute hospitalization period, multiple prior
• Hepatic failure < 50  109 cells/La studies have shown that the incidence of mostly asymptomatic
• Rheumatic disease • Advanced age > 85 y
• Active gastroduodenal • Dual antiplatelet therapya DVT ranges from 10 to 26% in general medical inpa-
ulcera • Male sex tients.11,44,45 The incidence of symptomatic VTE in unselected
• Prior stroke medically ill populations hospitalized in the U.S. has varied
• Malignancya from approximately 0.4 to 1.9%.15,38,46 Although low autopsy
• ICU/CCU stay rates make it difficult to determine the exact incidence of fatal
Abbreviations: CCU, critical care unit; CrCL, creatinine clearance; ICU, PE in this population, studies report incidences ranging from
intensive care unit. 2.5 to 7.6%.10,47 Assuming that a threshold risk of symptomatic
a
Key bleed risk factors (including MAGELLAN subpopulation). VTE of 1.0% is clinically meaningful, as many as half or more of

Thrombosis and Haemostasis Vol. 120 No. 6/2020

928 Venous Thromboprophylaxis in Medically Ill Patients
Fig. 1 Individualized (patient level) risk-adapted thromboprophylaxis in medically ill patients.
hospitalized medical patients in the U.S. are at risk of VTE
during their acute hospitalization period.9,43
The immediate posthospital discharge period is an especially
vulnerable period for VTE in medically ill patients, where the
rate of symptomatic VTE more than doubles over the first
21 days postdischarge and is associated with a fivefold increase
in fatal PE within 45 days.36 The incidence of symptomatic VTE
during the first 60 days or so after hospital discharge in North
American medically ill populations has varied from approxi-
mately 1.4 to 2.8%.17,31 Longitudinal data reveal that more than
half of all VTE events in this population occur posthospital
discharge.9,17 Recent modeling estimates show that at least 25
to 40% of medically ill patients are at high risk of VTE in the
posthospital discharge period.2,43
Individualized Thromboprophylactic Strategies
during Acute Hospitalization (up to 14 days) in
Medically Ill
Older randomized trials with UFH in hospitalized medical
patients based on mortality endpoints revealed a significant
30% risk reduction in all-cause mortality and fatal PEs in favor
of UFH, although more recent meta-analyses on the subject
revealed anticoagulant prophylaxis had no effect on all-cause
mortality (relative risk [RR] 0.97 [CI, 0.79–1.19).48–50 Placebo-
controlled trials that included patients over 40 years of age,
Thrombosis and Haemostasis Vol. 120 No. 6/2020
Spyropoulos et al.
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immobility, and additional VTE risk factors compared placebo
groups to the LMWHs enoxaparin 40 mg subcutaneously daily
and dalteparin 5000 IU subcutaneously daily, or the pentasac-
charide fondaparinux 2.5 mg subcutaneously daily with pri-
mary efficacy endpoints that were based mostly on lower
extremity venographic or ultrasonographic endpoints.11–13
These trials have shown a 50 to 60% reduction in total VTE
with a trend toward a numeric excess in MB events. All of these
studies had a 6- to 14-day treatment duration. Meta-analyses
revealed an approximately 60% reduction in any PE (RR 0.43,
95% CI, 0.26–0.71) and fatal PE (RR 0.38, 95% CI, 0.21–0.69) and
a nonsignificant reduction in DVT with heparin-based in-
hospital thromboprophylaxis.50
Using GRADE methodology, the 2012 American College of
Chest Physician guidelines recommended the use of in-hospital
LMWH, UFH three times a day or two times a day, or fondapar-
inux for acutely ill medical patients at increased risk of
thrombosis.14 The same guidelines recommended against anti-
coagulant prophylaxis for medically ill patients who are bleed-
ing or at high risk of bleeding.14 The 2018 American Society of
Hematology (ASH) guidelines defined a “patient-centered” end-
point that was a component of the primary endpoint of those
thromboprophylactic trials, namely symptomatic VTE and VTE-
related death, and provided a conditional recommendation that
suggested the use of LMWH, UFH, or fondaparinux in acutely ill
 Venous Thromboprophylaxis in Medically Ill Patients
medical patients,23 with the suggestion to use LMWH or fonda-
parinux over UFH.23 The same guidelines recommended using
LMWHs over DOACs for VTE prophylaxis, mainly due to an
increase in MB.
One key issue in these latest 2018 ASH guideline statements
is the use of the term “inpatient” to describe the duration of
hospital-based thromboprophylaxis. All of the recent placebo-
controlled trials of thromboprophylaxis in medically ill have
studied the efficacy and safety of LMWH for a duration of at least
6 to 14 days.32 As hospital length-of-stay in U.S. health systems
for medically ill has decreased to approximately 4.5 days,15 and
as fewer than 4 to 8% of medical patients receive any type of
posthospital discharge thromboprophylaxis,16,17 a potential
public health concern stems from the short duration of throm-
boprophylaxis suggested by these guideline statements.
The Food and Drug Administration (FDA) has approved the
LMWHs enoxaparin and dalteparin for thromboprophylaxis
for a total of 6 to 14 days, and both betrixaban 80 mg daily, and
more recently, rivaroxaban 10 mg daily, for VTE prophylaxis
for both inpatient as well as extended posthospital discharge
thromboprophylaxis in medically ill for 31 to 39 days.51–53
Data from both the inpatient portions of the APEX trial with
betrixaban and that from a post hoc analysis of the MAGELLAN
trial that excluded a subgroup of patients with five key
bleeding risk factors revealed similar efficacy and safety of
these DOACs when compared with the standard-of-care agent
enoxaparin 40 mg daily given for 6 to 14 days.19,21 In addition,
nonadministration of in-hospital VTE prophylaxis due to poor
patient adherence with parenteral heparin-based therapies is
problematic in U.S. health care settings, a concern that may be
ameliorated by use of oral-only options.54
Individualized Thromboprophylactic Strategies
during the Posthospital Discharge Period (30–45
Days) in Medically Ill
Five randomized controlled trials have studied extended
thromboprophylaxis in medically ill patients comparing
extended posthospital discharge prophylaxis with the LMWH
enoxaparin 40 mg subcutaneously daily or the DOACs apixaban
2.5 mg twice daily, rivaroxaban 10 mg daily, and betrixaban
80 mg daily to standard of care enoxaparin 40 mg subcutane-
ously daily given for 6 to 14 days or placebo postdi-
scharge.19,20,55–57 All studies enrolled patients aged
40
years with an acute medical illness, immobility criteria, and
added VTE risk factors. The most recent of these trials (APEX and
MARINER) also included elevated Dd as part of their inclusion
criteria, and MARINER included a modified IMPROVE VTE RAM
to define added VTE risk.19,20 All trials except MARINER
assessed total VTE mostly based on screening lower extremity
ultrasonography. The results were mixed. The EXCLAIM trial
with enoxaparin revealed net clinical benefit in certain patient
subgroups (including those aged > 75 years, female, and severe
immobility) but only after a major protocol amendment, while
the ADOPT trial with apixaban failed to show efficacy.55,56
The APEX trial with betrixaban narrowly missed its
primary efficacy endpoint of total VTE in the first cohort
studied of Dd positive patients (p ¼ 0.054), but showed
efficacy in key exploratory analyses including the overall
Spyropoulos et al. 929
population (RR 0.76, 95% CI, 0.63–0.92) without an increase
in bleed risk.19 APEX revealed a significant decrease in an
exploratory analysis of symptomatic VTE (RR 0.64, 95% CI,
0.42–0.98).19 There also was a 63% reduction of VTE-related
hospitalization with betrixaban (hazard ratio [HR] 0.33, 95%
CI, 0.16–0.71).58 The MAGELLAN trial with rivaroxaban met
both of its coprimary endpoints but revealed an almost
threefold increase in the risk of MB, including numerically
greater number of fatal bleeds compared with the
comparator.57
A post hoc analysis of the MAGELLAN trial that formed the
basis of its regulatory submission revealed that removal of five
key bleeding risk factors (including bronchiectasis/pulmonary
cavitation, active cancer, active gastroduodenal ulcer or history
of bleeding within 3 months, and dual antiplatelet therapy)
maintained the efficacy of rivaroxaban but reduced the major
bleed rates by half in both treatment phases so that MB was not
significantly worse with rivaroxaban (day 10, RR 1.19, 95% CI,
0.54–2.65; day 35, RR 1.48, 95% CI, 0.77–2.84).21 The analysis
also showed numerical reductions in the number of fatal bleeds
with rivaroxaban.21 Of note, the APEX trial also incorporated
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these key bleeding risk factors as part of its exclusionary
criteria.19 The largest trial, MARINER, failed to meet its primary
efficacy endpoint but revealed significant reductions in
key secondary endpoints including symptomatic VTE (HR
0.44, 95% CI, 0.22–0.89) and the combination of symptomatic
VTE and all-cause mortality (HR 0.73, 95% CI, 0.54–0.97).20 The
trial met its primary efficacy endpoint in the subgroup of
patients given a 3- to 6-day course of thromboprophylaxis
(HR 0.55, 95% CI, 0.31–0.97), which reflects U.S. hospital
treatment patterns.15,20 MB was very low and not different
in the two groups, and the trial excluded the five key bleeding
risk factors of the MAGELLAN subgroup mentioned.
A meta-analysis of 40,247 patients comparing the five trials
of standard duration versus extended thromboprophylaxis
using only the endpoints of symptomatic VTE and VTE-related
death found that extended thromboprophylaxis reduced this
endpoint by approximately 40% (1.2% vs. 0.8%, RR 0.61, 95% CI,
0.44–0.83) but that this benefit was partly offset by an
approximately twofold increased risk of MB or fatal bleeding
(0.3% vs. 0.6%, RR 2.04, 95% CI, 1.42–2.91).59 However, another
meta-analysis of the same trials focusing on more severe
outcomes found a 27% decreased risk of symptomatic nonfatal
PE and VTE-related death (RR 0.73, 95% CI, 0.57–0.93, absolute
risk reduction 0.25%, number needed to treat [NNT] 403)
without a significant increase in critical site or fatal bleeding
(RR 1.42, 95% CI, 0.41–4.91, absolute risk increase 0.056,
number needed to harm [NNH] 1,785) with extended throm-
boprophylaxis.60 Both analyses showed no differences in VTE-
related death between standard duration and extended
thromboprophylaxis.59,60 Recent risk–benefit analyses with
both betrixaban and rivaroxaban have established a favorable
net clinical benefit using appropriate severity of efficacy and
safety outcome pairings.21,61 In the APEX trial, a bivariate
analysis of both efficacy and safety of betrixaban revealed a
net clinical benefit of –0.51% (95% CI, –0.89 to –0.1%) over the
comparator.61 In the MAGELLAN subgroup analysis, the NNT to
prevent a composite of total VTE and VTE-related death was
Thrombosis and Haemostasis Vol. 120 No. 6/2020
930 Venous Thromboprophylaxis in Medically Ill Patients
55, whereas the NNH for a MB was 560.21 The NNT for a
symptomatic VTE and VTE-related death was 272, whereas the
NNH for a MB was 455; and the NNT and NNH for VTE-related
death versus a fatal bleed was 295 versus 1,067, respectively.21
The most recent antithrombotic guidelines (ASH 2018)
using a further modified version of GRADE methodology
gave a strong recommendation on the use of inpatient throm-
boprophylaxis with LMWH only rather than inpatient and
extended thromboprophylaxis with a DOAC.23 However, these
guidelines did not use the original study endpoints of total VTE
that included asymptomatic proximal DVT.23 Of note, consis-
tent data from three trials of medically ill thromboprophylaxis
now reveal a significant association between asymptomatic
proximal DVT found on screening ultrasonography and an
increased risk of all-cause mortality, indicating that this was
an appropriate component of the primary efficacy endpoint
used in trials of extended thromboprophylaxis.62–64 There was
no such association of an increased risk of mortality with distal
DVT.62,63 These guidelines also failed to establish whether
there was net clinical benefit in favor of extended thrombo-
prophylaxis in key low bleed risk patient subgroups and
defined high VTE risk populations as seen in the MAGELLAN
subpopulation, APEX, and MARINER trials. An earlier guideline
favored an individualized approach to extended thrombopro-
phylaxis in key subgroups of medically ill patients (age > 75
years, female, severe immobility).22
On the basis of a favorable net clinical benefit in the
modified intent-to-treat overall population in APEX of which
there was an evaluable efficacy outcome event, as well as a
favorable net clinical benefit in the MAGELLAN subpopulation
in which the high bleed risk subgroups with five key bleed risk
factors was removed (20% of the population), the FDA has
approved both betrixaban 160 mg followed by 80 mg orally
daily and rivaroxaban 10 mg orally daily for both inpatient as
well as extended posthospital discharge thromboprophylaxis
(31 up to 39 days) in hospitalized medically ill patients.51,53
Patients included in these trials were
40 years with an acute
medical illness, immobility, and had added VTE risk factors.60
Added VTE Risk Factors in High-Risk
Medically Ill Patients for Extended
Thromboprophylaxis
The MAGELLAN trial included added VTE risk factors such as
age
75 years, a history of heart failure, a history of cancer,
chronic venous insufficiency, body mass index
35 kg/m2,
severe varicosities, a history of VTE, use of hormone replace-
ment therapy, recent major surgery or serious trauma (6–12
weeks), and known thrombophilia.57 A post hoc analysis sub-
sequently defined elevated Dd as an additive VTE risk factor.34 A
recent subanalysis of the MAGELLAN database also established
that the modified IMPROVE VTE RAM with a cutoff score of
4
or a score of 2 or 3 with elevated Dd (as used in the MARINER
trial) identified a nearly threefold higher VTE risk subpopula-
tion of patients with a significant benefit for extended throm-
boprophylaxis.40 The APEX trial included age
75years, a
history of cancer or VTE, and an elevated Dd as the key additive
VTE risk factors.19 A post hoc analysis of the APEX trial using a
Thrombosis and Haemostasis Vol. 120 No. 6/2020
Spyropoulos et al.
modified IMPROVE VTE RAM that incorporated a score of 2 for
elevated Dd (the IMPROVEDD VTE RAM) also identified a
population with a > twofold higher VTE risk (HR 2.74, 95% CI,
1.52–4.90) than those with a score of 0 to 1.39 Lastly, the
MARINER trial that also used a modified IMPROVE VTE
score of
4 or a score of 2 or 3 with elevated Dd as part of
the inclusionary criteria found that the observed VTE incidence
in the placebo group (1.1%) identified an at-VTE risk population,
although it was lower than the expected 2.0 to 2.5% incidence.32
The totality of evidence suggests that key VTE risk factors such
as previous history of VTE, cancer, known thrombophilia,
elevated Dd, advanced age, and severe immobility or lower
extremity paresis either as independent risk factors or as part of
a VTE RAM such as the modified IMPROVE (cut off score
4)
predict a high VTE risk population that would benefit from
extended thromboprophylaxis (►Tables 1 and 3).
Key Secondary Outcomes with Extended
Thromboprophylaxis in Medically Ill
Patients and Populational Implications
Downloaded by: Karolinska Institutet. Copyrighted material.
An association between atherosclerosis/arterial thromboem-
bolism and VTE has been well described, but until recently
trials in VTE prevention in medically ill populations were
underpowered to see treatment effects.65 In addition, the
concept of reductions in irreversible and fatal events such as
cardiopulmonary death, myocardial infarction (MI), nonfatal
PE, and ischemic stroke, when assessing overall net clinical
benefit of thromboprophylatic strategies, has been estab-
lished.66–68 In a prespecified outcome, extended thrombopro-
phylaxis with betrixaban significantly reduced all-cause
stroke (0.72% vs. 1.48%, RR 0.49, 95% CI, 0.26–0.90, NNT 132)
and ischemic stroke (0.63% vs. 1.38%, RR 0.45, 95% CI, 0.24–
0.87, NNT 134) compared with standard duration prophylax-
is.66 In another APEX substudy, extended thromboprophylaxis
in all patients with betrixaban reduced irreversible and fatal
events (including at 35–42 days [4.08% vs. 2.90%, HR 0.71,
p ¼ 0.006, NNT 86]) compared with standard duration throm-
boprophylaxis.67 In a prespecified secondary outcome with
MARINER, extended thromboprophylaxis with the 10 mg dose
of rivaroxaban significantly reduced major and fatal vascular
events at 45 days (1.28% vs. 1.77%, HR 0.72, 95% CI, 0.52–1.00,
p ¼ 0.049, NNT 204).69 Lastly, pooled analysis for extended
thromboprophylaxis with rivaroxaban revealed a reduction
(2.31% vs. 1.70%, HR 0.78, p ¼ 0.024, NNT 197) in major
thromboembolic events and all-cause mortality.70
Assuming a large proportion of the approximately 7.2
million hospitalized medically ill patients in the U.S. are both
at-risk for hospital-based VTE and at high risk for posthospi-
tal discharge events, then extended thromboprophylaxis
with betrixaban or rivaroxaban has major populational
health implications in U.S. health systems.21,67 Applying
reductions in symptomatic VTE seen in the APEX trial with
betrixaban would result in approximately 20,000 fewer
symptomatic VTEs and the potential to result in 12,000
fewer VTE-related deaths.71 Data based on the MAGELLAN
subgroup suggests that in the European Union and U.S.
health systems, a strategy of extended thromboprophylaxis
 Venous Thromboprophylaxis in Medically Ill Patients
with rivaroxaban versus standard in-patient thrombopro-
phylaxis has the potential to prevent symptomatic VTE
and VTE-related death in approximately 24,000 patients
annually and to prevent irreversible and fatal vascular events
in approximately 12,000 patients annually, at the cost of
incurring MB in approximately 6,000 patients and fatal
bleeding in approximately 3,000 patients each year.21
Health Informatics Technology and
Electronic/Physician Alerts at Hospital
Admission and Discharge in Medically Ill
Electronic health records (EHRs) are now ubiquitous. The use of
health informatics technology, especially embedding electron-
ic order alerts for clinical prediction rules such as VTE RAMs in a
hospital-based clinician’s workflow, have the potential to
impact care delivery, allow enhanced adoption of a prediction
rule, and ultimately improve clinical outcomes.72,73 Random-
ized trials using electronic or physician alerts associated with a
VTE RAM versus usual medical care in hospitalized medically ill
patients have significantly increased rates of appropriate
thromboprophylaxis by approximately twofold.74–76 These
efforts have included use of electronic or physician alerts
both at hospital admission, and also at hospital discharge74–76
One such study using electronic alerts linked to a computer
program using a scored VTE RAM revealed an approximately
50% increase in the relative rate of pharmacological prophylax-
is (23.6% vs. 13%, p < 0.001) coupled with a 41% reduction in the
risk of VTE (HR 0.59, 95% CI, 0.43–0.81, p ¼ 0.001).74
Proposed Clinical Pathways on The Use of
In-Hospital and Extended Postdischarge
Thromboprophylaxis in Acute Medically Ill
Patients
Based on the best available data, we propose the following
clinical pathways on the use of in-hospital and extended
thromboprophylaxis for acute medically ill patients in U.S.
health systems. The first series of statements pertain to
hospital admission and hospital stay, including stay in the
ICU/critical care unit:
Statement 1: A formalized and standardized VTE and
bleed risk assessment should be administered in every
hospitalized medically ill patient both at admission and
during a change in clinical status or change in level of care
during hospitalization. VTE risk assessment can include
RAMs such as the modified IMPROVE VTE and Padua VTE
RAMs.
Qualifying Statement: Whenever possible, admission
electronic or physician alerts coupled with a VTE RAM
should be considered.
Statement 2: Medically ill patients over 40 years of age at
risk for VTE defined by:
(a) an admission with exacerbation of CHF, respiratory
insufficiency, cancer, acute stroke, acute infection/sepsis,
or autoimmune/rheumatic disease with immobility and
(b) at least one key VTE risk factor or
Spyropoulos et al. 931
(c) a modified IMPROVE VTE score of
2/Padua VTE
score
4 and
are not an increased risk for bleeding defined by:
(a) the absence of one key clinical or laboratory-based risk
factor for bleeding including
i. gastroduodenal ulcer or a history of any bleeding
within the previous 3 months
ii. creatinine clearance less than 30 mL/min
iii. active cancer (especially gastrointestinal and genito-
urinary cancers)
iv. bronchiectasis/pulmonary cavitation
v. dual antiplatelet therapy which cannot be discontinued or
(b) an IMPROVE bleed score of < 7
are candidates for pharmacological thromboprophylaxis.
Qualifying Statement: Whenever possible, at admission
electronic or physician alerts coupled with a VTE RAM
should be considered.
Downloaded by: Karolinska Institutet. Copyrighted material.
Statement 3: Medically ill patients who are candidates for
pharmacological thromboprophylaxis should receive low-dose
UFH (5000 IU two times a day/three times a day), LMWH
(enoxaparin 40 mg subcutaneously daily, dalteparin 5000 IU
subcutaneously daily), pentasaccharide fondaparinux (2.5 mg
subcutaneously daily) or the DOACs betrixaban 160 mg orally
initial dose followed by 80 mg orally daily, or rivaroxaban
10 mg orally daily. The duration for UFH, LMWH, or fondapar-
inux should be at least 6 and up to 14 days, regardless of the
duration of hospitalization.
Statement 4: If patients are not candidates for pharmaco-
logical thromboprophylaxis, then at-VTE risk patients should
receive mechanical means of thromboprophylaxis including
graduated compression stockings and intermittent pneu-
matic compression devices.
These next series of statements pertain to the hospital
discharge and immediate posthospital discharge period (30
to 45 days):
Statement 5: As part of hospital discharge planning,
medically ill patients at risk of VTE should be assessed for
the benefit and risk of extended pharmacological thrombo-
prophylaxis. Medically ill patients as defined at admission,
during hospitalization, or at discharge that have at least one
of the following key VTE risk factors:
(a) Age
75 years
(b) A history of VTE
(c) A history of cancer
(d) Elevated Dd > 2 ULN
(e) A modified IMPROVE VTE score of
4 and
are not an increased risk for bleeding defined by:
(a) the absence of one key clinical or laboratory-based risk
factor for bleeding including
i. gastroduodenal ulcer or a history of any bleeding
within the previous 3 months
ii. creatinine clearance less than 30 mL/min
Thrombosis and Haemostasis Vol. 120 No. 6/2020
932 Venous Thromboprophylaxis in Medically Ill Patients Spyropoulos et al.

iii. active cancer (especially gastrointestinal and genito-
urinary cancers)
iv. bronchiectasis/pulmonary cavitation
v. dual antiplatelet therapy which cannot be discontinued
are candidates for extended pharmacological thrombo-
prophylaxis.
either the DOAC betrixaban 80 mg orally daily or rivaroxaban
10 mg orally daily for a duration of approximately 31 to 39 days.
These statements are depicted on the clinical pathways
we propose for an individualized, risk-adapted approach to
thromboprophylaxis in medically ill patients as shown
in ►Fig. 2A , B.

Discussion and Implications

Qualifying Statement: Whenever possible, at discharge
electronic or physician alerts coupled with a VTE RAM
should be considered.
Statement 6: Medically ill patients that are candidates for
extended pharmacological thromboprophylaxis should receive
The population of medically ill patients in U.S. hospitals
tends to be elderly, to have multiple comorbidities, and to
have poor in-hospital adherence to parenteral therapies.16,54
In addition, given the comparatively short hospital length-

Downloaded by: Karolinska Institutet. Copyrighted material.

Fig. 2 (A) In-hospital venous thromboembolism (VTE) risk assessment on admission. (B) In-hospital VTE risk assessment on discharge. Active cancer,
bronchiectasis, a history of recent bleed within 3 months, dual antiplatelet therapy, active gastroduodenal ulcer. Needs external validation.

Thrombosis and Haemostasis Vol. 120 No. 6/2020

 Venous Thromboprophylaxis in Medically Ill Patients
Fig. 2 (B) (Continued)
of-stay in the U.S. for this population coupled with a lack of
routine posthospital discharge thromboprophylaxis, the ma-
jority of at-VTE risk as well as high-VTE risk medically ill
patients are given inappropriately short durations of throm-
boprophylaxis.15 This remains a key reason for the failure of
many hospital-based quality improvement efforts to lower
hospital-acquired VTE in this population.15 The advent of
oral-only options for thromboprophylaxis, namely the
DOACs betrixaban and rivaroxaban, which are FDA-approved
for both in-hospital as well as posthospital discharge extend-
ed thromboprophylaxis, has potential to improve adherence
to in-hospital VTE prevention, and decrease VTE in selected
high VTE risk populations.
The concept of net clinical benefit from extended throm-
boprophylaxis in medically ill patients has undergone fur-
ther refinement since the publication of the most recent
antithrombotic guidelines.23 Both efficacy and safety data
have to be weighed according to the degree of their clinical
severity and impact. Data now reveal a clear association
between asymptomatic lower extremity proximal DVT found
by screening ultrasonography and all-cause mortality in this
population.21,63 In addition, the reduction of all irreversible
and fatal thromboembolic events, including arterial events,
in assessing net clinical benefit from a thromboprophylactic
strategy is gaining prominence in academic and regulatory
environments.68 As such, whether using bivariate analyses,
pairwise comparisons of efficacy and safety outcomes with
similar clinical severities, or assessment of irreversible and
fatal thromboembolic events, a strategy of extended throm-
Spyropoulos et al. 933
Downloaded by: Karolinska Institutet. Copyrighted material.
boprophylaxis in carefully selected subpopulations of medi-
cally ill patients has the potential to prevent 2 to 10 major or
fatal thromboembolic events (including nonfatal PE, MI,
stroke, and cardiovascular death) for every serious or fatal
bleed incurred.21,61,67 This has major populational health
implications in U.S. health systems, where estimates suggest
that approximately 25 to 40% of the 7.2 million medically ill
patients are at sufficient VTE risk to benefit from extended
thromboprophylaxis.2,18
Lastly, health informatics technology is evolving. The capa-
bility exists to incorporate validated clinical prediction rules
such as VTE RAMs into a hospital-based clinician’s workflow
within an EHR applications based on newer informatics tech-
nologies such as “SMART on FHIR.”77 These informatics tech-
nologies have potential to launch clinical prediction rules such
as VTE RAMs linked to an electronic order entry for an
appropriate type and duration of a thromboprophylactic
agent, within the workflow of any EHR (i.e., EHR agnostic).
This allows the interoperability of health informatics technol-
ogy and EHRs as well as enhanced adoption, acceptance, and
dissemination of key VTE risk factors and/or VTE RAMs. These
efforts may potentially reduce hospital-acquired VTE—both in-
hospital as well as posthospital discharge—in hospitalized
medically ill patients as part of quality improvement efforts.
The field of thromboprophylaxis of the hospitalized med-
ically ill patients is complex, with heterogeneous patient
populations and involvement of multiple medical specialties.
We provide a framework by which an evidence-based, risk-
adapted, and individualized (patient-centered) approach to
Thrombosis and Haemostasis Vol. 120 No. 6/2020
934 Venous Thromboprophylaxis in Medically Ill Patients
thromboprophylaxis in acutely ill medical patients can be
implemented. As more clinical data become available, there
should be ongoing clarification concerning many of the
current research and clinical questions of thromboprophy-
laxis in this population.
Conflict of Interest
A.C.S.: Consultant – Janssen, Bayer, Boehringer Ingelheim,
Portola, ATLAS Group; Research support – Janssen, Boeh-
ringer Ingelheim; W.A.: Honoraria from Boehringer Ingel-
heim, Bayer Pharmaceuticals, BMS-Pfizer, Sanofi, Portola,
and Daiichi-Sankyo; Research support from Bayer; A.T.C.:
AbbVie, ACl Clinical, Aspen, Bayer, Boehringer-Ingelheim,
Bristol-Myers Squibb, Boston Scientific, BTG, CSL Behring,
Daiichi-Sankyo, GlaxoSmithKline, GLG, Guidepoint Glob-
al, Johnson and Johnson, Leo Pharma, Medscape, McKin-
sey, Navigant, ONO, Pfizer, Sanofi, Takeda, Temasek
Capital, TRN; Research grant support – Portola; C.M.G.:
Research grants support Janssen, Bayer, Portola; Consult-
ing Janssen, Bayer, Portola; S.Z.G.: Research grant support
– Portola, Bio2Medical, Boehringer-Ingelheim, BMS, BTG
EKOS, Daichi, Janssen, National Heart Lung and Blood
Institute; Consulting – Bayer, Boehringer-Ingelheim,
BMS, Daichi, Janssen, and Portola; G.R.: Consulting/Hon-
oraria – Janssen, Bristol Meyer Squibb, Daichi Sankyo,
Medscape, Pfizer; Consultant – Bayer Healthcare, Boeh-
ringer Ingelhein, Eli Lilly, Merck, Novartis, Portola, and
Tetherex. A.C.S. reports grants and personal fees from
Janssen, personal fees from Bayer, grants and personal
fees from Boehringer Ingelheim, personal fees from Por-
tola, personal fees from ATLAS Group, during the conduct
of the study. W.A. reports grants and personal fees from
Bayer, personal fees from Boehringer Ingelheim, personal
fees from BMS-Pfizer, personal fees from Daiichi Sankyo,
personal fees from Aspen, personal fees from Sanofi,
personal fees from Portola, personal fees from Janssen,
outside the submitted work . G.R. reports personal fees
from Janssen, personal fees from Bayer, during the con-
duct of the study; personal fees from BMS, personal fees
from Boehringer Ingelheim, personal fees from Daiichi
Sankyo, personal fees from Eli Lilly, personal fees from
Pfizer, personal fees from Itreas Clinical Research, person-
al fees from Portola, personal fees from Tetherex, personal
fees from XaTek, outside the submitted work.
Acknowledgments
We would like to acknowledge Kira MacDougall, MD, for
her assistance in the drafting of this manuscript, and
especially the figures and tables.
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