Ven o u s T h ro m b o e m b o l i s m

P re v e n t i o n i n t h e
Hospitalized Medical Patient
Nikolaos Tsaftaridis, MDa,b, Anthony Cholagh, DOc,
Scott Kaatz, DOd,e,f, Alex C. Spyropoulos, MDa,b,g,*

KEYWORDS
 Anticoagulants  Deep vein thrombosis  Pulmonary embolism
 Venous thromboembolism thromboprophylaxis  Thrombosis risk factors
 Risk assessment models  Hospitalized medical patients

KEY POINTS
 All acutely ill medical inpatients should undergo formal venous thromboembolism (VTE)
risk assessment with individual VTE risk factors or validated VTE risk models to assess
need for thromboprophylaxis.
 Patients with high individual VTE risk factors or meeting VTE model thresholds (Padua
score of 4 or IMPROVE/IMPROVE-DD score of 2) with a low-bleeding risk require
thromboprophylaxis at admission.
 Inpatient thromboprophylaxis with once-daily LWMH (enoxaparin 40 mg/dalteparin 5000
IU) if no renal impairment or twice- or thrice-daily UFH in those with renal impairment is
acceptable.
 VTE risk extends up to 45 days from discharge in high risk patient profiles (IMPROVE/
IMPROVE-DD score of 4).
 If a patient is at high VTE risk and low bleed risk, they should be considered for extended
postdischarge thromboprophylaxis with rivaroxaban.

INTRODUCTION AND EPIDEMIOLOGY

Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pul-
monary embolism (PE), is the third most common vascular disease globally.

a
Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell, New
Hyde Park, NY, USA; b Institute of Health System Science, Feinstein Institutes for Medical
Research, Manhasset, NY, USA; c Internal Medicine, Henry Ford Health System, Detroit, MI,
USA; d Division of Hospital Medicine, Henry Ford Health System, Detroit, MI, USA; e Michigan
State University – College of Human Medicine, Detroit, MI, USA; f Wayne State University –
School of Medicine, Detroit, MI, USA; g Donald and Barbara Zucker School of Medicine at
Hofstra/Northwell, Hempstead, NY, USA
* Corresponding author. Northwell Health Physician Partners Medicine Specialties at East 85th
Street, 178 E 85th Street, 2nd Floor, New York, NY 10028.
E-mail address: aspyropoul@[Link]

Med Clin N Am - (2025) -–-

[Link] [Link]
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2 Tsaftaridis et al

Abbreviations
BMI body mass index
CrCl creatinine clearance
CRNMB clinically relevant nonmajor bleeding
DOAC direct oral anticoagulants
DVT deep vein thrombosis
EHR electronic health record
GCS graduated compression stockings
ICU intensive care unit
IPC intermittent pneumatic compression
LMWH low molecular weight heparin
LOS length of stay
OR odds ratio
PE pulmonary embolism
RAM risk assessment models
VTE venous thromboembolism

Approximately 50% of all VTE occur as a result of a recent hospitalization with acute
medical illness representing 22% of these VTE events.1 In the United States, approx-
imately 8 million medical inpatients are at risk for VTE annually, with an annual inci-
dence estimated at 1.22 million cases per year2,3 and a concomitant financial
burden of $7 to $10 billion for the US health care system.4
Acutely ill, medical (nonsurgical) patients are older and more comorbid compared to
surgical patients at baseline hospitalization5 and are more likely to present with more
proximal and severe forms of VTE—with higher morbidity and mortality—compared to
surgical patients.5,6 They represent 50% to 70% of symptomatic VTE and 70% to 80%
of fatal PE cases in the hospital. Hospitalized medical inpatients are heterogeneous,
with a cumulative incidence of symptomatic VTE from admission up to 45 days post-
discharge that varies from around 1% in low to moderate VTE risk populations to
greater than 4% in high VTE risk populations.1,7
Modeling studies show that universal or group-based thromboprophylaxis strate-
gies inappropriately emphasize pharmacologic VTE prevention in as much as 50%
to 60% of low VTE risk medical inpatients and potentially subject them to harms of
bleeding and under-emphasize VTE prevention in as much as 25% of high VTE risk
medical inpatients by giving inadequate durations of thromboprophylaxis.7 Given
the heterogeneity of this population, medical inpatients require an individualized
approach to thromboprophylaxis.1
VTE prevention practices aim to mitigate VTE risk in individuals with an appropriate
risk-benefit balance.8 Broad interventions such as passive alerts and clinical decision
support tools can raise awareness of VTE risk factors, emphasize signs and symptoms
of VTE, and aid in VTE risk stratification and appropriate thromboprophylaxis,
decreasing VTE-related morbidity and mortality.8,9 This article presents a practical
approach to thromboprophylaxis for medical inpatients based on current evidence
and clinical practice guidelines,1,10 with a focus on US clinical practice patterns.

The Inpatient Period

Venous thromboembolism risk and risk assessment
Acute medical illness-related or disease-specific VTE risk factors as well as patient-
specific VTE risk factors (many of which are unmodifiable), coupled with immobility
usually caused by disease severity contribute to a medical inpatient’s overall risk of
VTE.11 However, VTE risk factors are not all weighted equally, with some consistently

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 Medical Inpatient Venous Thromboembolism Prevention 3

showing a strong association with increased risk of VTE in medical inpatients (“High
VTE Risk Factors”), while others less so (Table 1).12–14
Patient-specific risk factors such as advanced age, active cancer or recent history
of cancer, a history of thrombophilia or prior VTE have been associated with a high risk
of VTE. Disease-specific risk factors such as acute stroke, infection or sepsis, conges-
tive heart failure exacerbation, a stay in an intensive care unit (ICU), and acute inflam-
matory or pulmonary disease have also been associated with a high risk of VTE.
Recently, an elevated D-dimer (more than or equal to twice the upper limit of normal
based on local criteria) has been shown to be consistently associated with a high risk
of VTE.15 A group of VTE risk factors collectively called the “APEX criteria” have also
been proposed, and include age more than 75 years, past medical history of cancer or
VTE, and extra risk factors (comorbidities that are risk factors for VTE).16,17
Other risk factors have inconsistently shown risk of VTE (“Probable VTE Risk Fac-
tors”), while other VTE risk factors have not been thoroughly evaluated in epidemio-
logic studies (“Possible VTE Risk Factors”). These include obesity, chronic venous
insufficiency, and use of erythropoietin-containing medications. The risk of VTE also
increases with the accumulation of individual VTE risk factors.13,18

Formalized risk assessment models

VTE RAMs that are weighted and scored have been developed using observational
and clinical trial data and appropriately calibrating the model to consider the most
important VTE risk factors. VTE RAMs in hospitalized medical patients have included
the Kucher/Geneva score,19 Intermountain Score,20 the Caprini score,21 the Padua
Score,22 and the IMPROVE23 and IMPROVE-DD scores,24 and include scores ranging
from 1 to 4 points depending upon the weight of the individual risk factor.25 However,
only the Padua, IMPROVE, and IMPROVE-DD VTE RAMs (Table 2) have undergone
extensive external validation in a variety of medical inpatient settings, including pa-
tients with Coronavirus Disease 2019 (COVID-19) for the IMPROVE-DD VTE RAM
and with reference to prespecified criteria as endorsed by antithrombotic guide-
lines.1,10,26 The IMPROVE and IMPROVE-DD RAMs have a trinary VTE risk scheme
that can identify high-VTE risk patients that benefit from extended postdischarge
thromboprophylaxis.27 Both the Padua, IMPROVE, and IMPROVE-DD VTE scores
have been endorsed by guidelines such as those of the American Society of Hematol-
ogy, the International Society of Thrombosis and Hemostasis, and the International
Union of Angiology.1,10,26 Large scale external validation studies have shown AUCs
of 0.64 for PADUA and up to 0.73 with the IMPROVE score.28,29 Both scores incorpo-
rate the following risk factors: age, previous VTE, known thrombophilia, mobility, and
cancer. The Padua score also incorporates acute medical illness such as acute
myocardial infarction, stroke, acute infection, or rheumatologic disease as well as
obesity, while the IMPROVE score incorporates leg paresis as a surrogate of severe
stroke and stay in a critical care unit. The IMPROVE-DD score additionally incorpo-
rates elevated D-dimer (2x the upper limit of normal) as a novel biomarker. A score
of 4 or more in the Padua score and a score of 2 in the IMPROVE and IMPROVE-DD
scores have shown symptomatic VTE rates of greater than 1 to 2% and identify a
candidate for inpatient thromboprophylaxis, while a score of 4 or more using the
IMPROVE or IMPROVE-DD scores have shown symptomatic VTE rates of more
than 4% and identify a candidate for extended postdischarge thromboprophylaxis.

Bleeding risk assessment

Bleeding risk that includes patient-specific, disease-specific, and laboratory variables
is important to determine overall net clinical benefit when determining a

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Tsaftaridis et al
Table 1
Risk factors for venous thromboembolism in hospitalized medical patients

High VTE Risk Factors Probable VTE Risk Factors Possible VTE Risk Factors
 History of VTE  High-dose estrogen  Paraproteinemia
 Acute Infection  BMI >25  Bechet’s disease
 Malignancy  Chronic venous insufficiency  Nephrotic syndrome
 Age >75  History of HIT  Polycythemia
 Congestive heart failure  PNH
 Stroke  Myeloproliferative disorder
 Shock/ICU Stay/Critical Illness  Age >40
 Elevated D-Dimer (>2x ULN)  Renal failure
 Immobility or Barthel index score 9  Collagen vascular disease
 Congenital/Acquired Thrombophilia  Erythropoiesis-stimulating agents
 Pregnancy/postpartum  CRP >10 mg/L
 Acute/chronic lung disease  Elevated pro-NT BNP
 Acute inflammatory or rheumatic disease
 Family history of VTE

Abbreviations: BNP, brain natriuretic peptide; CRP, C reactive protein; ULN, upper limit of normal.
VTE risk factors in bold font have been proven to be associated with a high risk of VTE. High risk factors: moderately supported by evidence. Probable risk factors:
disputed by some studies. Possible risk factors: not extensively epidemiologically evaluated.12–14
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Table 2
Comparison of well-validated venous thromboembolism risk assessment models in the acutely ill medical patient

Padua22 IMPROVE23 and IMPROVE-DD24

Risk Factors Points Risk Factors Points
Active cancer 13 Previous VTE 13

Medical Inpatient Venous Thromboembolism Prevention

Previous VTE 13 Known thrombophilia 12
Reduced mobility 13 Current lower-limb paralysis 12
Already known thrombophilic condition 13 Current cancer 12
Recent (1 mo) trauma and/or surgery 12 Immobilized 7 d (Immediately before and during hospital stay) 11
Elderly age (70) 11 ICU/CCU Stay 11
Heart and/or respiratory failure 11 Age >60 11
Acute MI and/or ischemic stroke 11 D-Dimer 2x ULNa 12
Acute infection and/or rheumatologic disorder 11
Obesity (BMI 30) 11
Ongoing hormonal treatment 11

RAMs compared in this table include the Padua, IMPROVE, and IMPROVE-DD. Padua: 4 points identify candidates for inpatient VTE prophylaxis. IMPROVE/
IMPROVE-DD: 2 points identify candidates for inpatient VTE prophylaxis, while a score of 4 identify candidates at high VTE risk for extended post-
discharge thromboprophylaxis.
a
D-dimer 2x upper limit of normal according to local laboratory reference value is an additional risk factor included in the IMPROVE-DD score but not in the
IMPROVE score. External validation: Padua score AUC 5 0.58- 0.64, IMPROVE score AUC 5 0.64-0.73, IMPROVE-DD score AUC 5 0.70.

5
6 Tsaftaridis et al

pharmacologic VTE prevention strategy in hospitalized medical patients. A collection

of 5 disease-specific or patient-specific bleeding risk factors, which included active
cancer, dual antiplatelet therapy at hospitalization, a recent history of bleeding or
active gastroduodenal ulcer within 3 months before hospitalization, or history bronchi-
ectasis or pulmonary cavitation, were strong independent predictors of both in-
hospital and immediate postdischarge risk of major and fatal bleeding.27 Individual
risk factors for bleeding along with their respective odds ratios are presented in
Table 3.30–32
Validated bleeding risk assessment model
The weighted and scored IMPROVE Bleed RAM30 remains the only extensively vali-
dated bleed RAM currently available for hospitalized medical patients. The score in-
cludes both disease-specific and laboratory-based variables, with individual risk
factors scored from 1 to 4.5 points. A score of lesser than 7 indicates low risk of major
or clinically relevant nonmajor bleeding (CRNMB), while a score of 7 or more indicates
high risk of bleeding.
A retrospective chart review was performed to evaluate the external validity of the
IMPROVE Bleed RAM involving 12,082 subjects. Rates of major bleeding, CRNMB,
and any bleeding were compared between high risk (7) and low risk (<7) groups.
There was a 2.12% rate of any bleeding in those patients with a score of less than 7
and a 4.68% rate in those with a score 7 [Odds Ratio (OR) 2.3 (95% confidence in-
terval [CI] 5 1.8–2.9), P<.0001]. Major bleeding rates were 1.50% in the patients with a
score of less than 7 and 3.20% in the patients with a score of 7, [OR 2.2 (95% CI 5
1.60–2.90), P<.0001].33 (Table 4)

Table 3
Risk factors for bleeding12,30-32

Risk Factor Odds Ratio (95% CI)

Anemia as reason for admission 5.15 (2.45–10.81)
Thrombocytopenia (<50  10⁹/L) 3.37 (1.84–6.18)
BMI 40 kg/m2 3.08 (1.35–7.02)
Gastroduodenal ulcers 2.74 (1.42–5.26)
Rehospitalization 2.39 (2.25–2.54)
Low hemoglobin (<13 g/dL in men, <11.5 g/dL in women) 2.33 (1.04–5.22)
Chronic kidney disease (stage 4 or lower, GFR <30 mL/min/m2) 2.14 (1.22–3.75)
Critical illness (ICU/CCU stay) 2.10 (1.42–3.11)
Age 65 vs <65 y 1.95 (1.59–2.38)
Thrombocytopenia (all) 1.79 (0.97–3.29)
Blood dyscrasias 1.70 (1.60–1.81)
Hepatic disease 1.53 (1.09–2.15)
Chronic kidney disease overall 1.43 (1.06–1.93)
Moderate renal failure (stage 3, GFR 30–59 mL/min/m2) 1.37 (0.84–2.23)
Central venous catheter 1.37 (0.83–2.26)
Thrombocytopenia (<150  10⁹/L) 1.30 (0.92–1.82)
Autoimmune disease 1.30 (0.77–2.19)
Male sex 1.27 (1.09–1.47)
Malignancy 1.08 (0.42–2.77)
Hormone use (estrogen) 0.95 (0.82–1.10)

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 Medical Inpatient Venous Thromboembolism Prevention 7

Inpatient thromboprophylaxis
Hospitalized medical patients that were included in landmark double-blind, random-
ized, placebo-controlled clinical trials were over 40 years of age with immobility criteria
and key acute medical illnesses (stroke, acute heart failure, acute respiratory failure,
acute rheumatic disease, inflammatory bowel disease, and active cancer) in addition
to key VTE risk factors (advanced age > 70 years, previous VTE, history of thrombo-
philia, high body mass index (BMI), varicosity, hormone therapy, myeloproliferative
syndrome, and a history of chronic respiratory or heart failure). The duration of throm-
boprophylaxis in these trials was 6 to 14 days.34–37
Baseline rates of total VTE (asymptomatic DVT, symptomatic VTE, and fatal VTE) in
groups of hospitalized medical patients ranged between 5% to 14.90%, with symptom-
atic VTE rates as high as 2.20% (Fig. 1).34–37 Although previous antithrombotic guide-
lines have emphasized symptomatic VTE as the most important outcome, more
recent data and guidelines confirm asymptomatic proximal DVT to be consistently asso-
ciated with mortality and important when assessing net clinical benefit of pharmacologic
thromboprophylaxis.10,38 Thromboprophylaxis with either a once-daily low molecular
weight heparin (LMWH) or the pentasaccharide fondaparinux conferred a 47% to
63% relative risk reduction of VTE.
The landmark MEDENOX trial evaluated 2 doses of enoxaparin 20 mg and 40 mg
quaque die (QD) subcutaneously (SQ) vs placebo and concluded that both were
safe compared to placebo, and the 40 mg dose was effective compared to placebo
(incidence 5.50% in the 40 mg group vs 14.90% in the placebo group, relative risk
(RR) 0.37, 97.60% CI: 0.22–0.63, P<.001), while the 20 mg dose was not (15% inci-
dence).34 The trial used venography to assess asymptomatic lower extremity DVT,
which is more sensitive than compression ultrasonography, explaining the higher
DVT rates seen in this trial when compared to trials that used lower extremity
compression ultrasound or only looked at symptomatic DVT events.

Table 4
The IMPROVE bleed risk score30

Risk Factor Score

Age, Years
 40–84 11.5
 >85 13.5
Male 11
Renal Function, GFR (ml/min/1.73 m2)
 30–59 11
 <30 12.5
Current Cancer 12
Rheumatic Disease 12
Central Venous Catheter 12
ICU/CCU 12.5
Evidence of Hepatic Failure (INR >2.5) 12.5
Platelet Counts, cell/L <50x109 14
Bleeding in last 3 mo before admission 14
Active gastroduodenal ulcer 14.5

Abbreviations: CCU, coronary care unit; GFR, glomerular filtration rate; HIT, heparin-induced
thrombocytopenia; INR, international normalized ratio; PNH, paroxysmal nocturnal
hemoglobinuria

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8 Tsaftaridis et al

RRR 63%
16.00 P<0.001

14.00

12.00 RRR 47%

P<0.003

10.00

8.00

RRR 49%
6.00 P<0.002

4.00

2.00

0.00
MEDENOX a Enoxaparin 40 PREVENT b Dalteparin 5000 ARTEMIS b Fondaparinux
mg QD (N=1102) IU QD (N=3706) 2.5 mg QD (N=849)
Placebo 14.90 5.00 10.50
Prophylaxis 5.50 2.80 5.60

Placebo Prophylaxis
Fig. 1. VTE incidence at day 14 for MEDENOX and PREVENT, day 15 for ARTEMIS.34,36,37 Sig-
nificant decreases are noted in VTE incidence across these landmark studies, establishing a
clear benefit for thromboprophylaxis over placebo. aTotal VTE including venography-
detected DVT, symptomatic VTE, and fatal VTE. bTotal VTE including asymptomatic proximal
DVT by ultrasonography, symptomatic VTE, and fatal VTE.

The PREVENT trial evaluated dalteparin 5,000 international units (IU) SQ daily for
14 days vs. placebo in 3,706 acutely ill medical patients. The primary outcome was
a composite of symptomatic DVT, symptomatic PE, asymptomatic proximal DVT
(detected by ultrasound at day 21), and sudden death by day 21. Dalteparin signifi-
cantly reduced VTE incidence compared to placebo (2.77% vs 4.96%, absolute risk
reduction: 2.19%, relative risk reduction (RRR): 45%, RR: 0.55, 95% CI: 0.38 to
0.80, P 5 .0015). This benefit was maintained at 90 days. Major bleeding was slightly
higher in the dalteparin group (0.49% vs 0.16%).36
The ARTEMIS trial evaluated fondaparinux 2.5 mg SQ daily for 6 to 14 days versus
placebo for VTE prophylaxis in 849 medical patients aged 60 years with moderate to
high-VTE risk. The primary outcome was VTE detected by routine bilateral venography
or symptomatic VTE up to day 15. Fondaparinux significantly reduced VTE incidence
compared to placebo (5.60% vs 10.50%, RRR: 46.70%, 95% CI: 7.70%-69.30%) and
major bleeding was similar. Mortality at follow-up was lower in the fondaparinux group
(3.3% vs 6.0%).37
A recent clinical trial conducted at French centers (SYMPTOMS trial) using only
symptomatic VTE as an outcome found no benefit of inpatient thromboprophylaxis
with LMWH in medical inpatients (cumulative incidence 1.80% in the enoxaparin vs

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 Medical Inpatient Venous Thromboembolism Prevention 9

2.20% in the placebo group, cumulative incidence difference 0.40%, 95% CI

-1.50%–0.70%, P 5 .46); however the trial was stopped early and was underpowered
for its conclusions.35
Meta-analyses have shown that inpatient heparin thromboprophylaxis have led to a
RRR of 53% in any PE and 62% in fatal PE, without a significant increase in major
bleeding.39

Extended Postdischarge Thromboprophylaxis

Longitudinal studies have consistently found that the risk of VTE extends up to 45 days
from hospital discharge, with the rate of symptomatic VTE more than doubling over the
first 21 days postdischarge.13,40,41 In addition, the majority of VTE in elderly medical
inpatients has been shown to occur in the postdischarge period.13,40 The shortened
hospital length of stay (LOS) in the United States and other countries has dampened
treatment effects of in-hospital thromboprophylaxis and thus, the disease burden of
VTE is shifting to the posthospitalization setting with shorter hospital stays.11,42 A
multihospital quality improvement study in the United States showed that despite a
30% absolute difference in inpatient thromboprophylaxis there has was no benefit
of VTE-free survival between low and high performing hospitals.42 One key reason
may have been the short LOS (mean LOS of 4.5 days) in these patients, and that
less than 4% of patients receive any type of postdischarge thromboprophylaxis.31,42
Five randomized controlled trials that studied extended thromboprophylaxis in
medically ill inpatients comparing extended posthospital discharge prophylaxis with
LMWH or direct oral anticoagulants (DOACs) including apixaban, rivaroxaban, and
betrixaban to standard of care inpatient enoxaparin given for 6 to 14 days in-
hospital or placebo postdischarge had mixed results (Fig. 2). All studies enrolled pa-
tients aged over 40 years with an acute medical illness, immobility criteria, and added
VTE risk factors. The MARINER trial included a modified IMPROVE VTE RAM to define
added VTE risk while both the APEX and MARINER trials included elevated D-dimer as
part of their inclusion criteria.16,43 All trials except MARINER assessed total VTE
mostly based on asymptomatic proximal DVT using screening lower extremity
ultrasonography.
The EXCLAIM trial demonstrated that extended-duration enoxaparin significantly
reduced VTE at 28 days compared to placebo (2.50% vs 4.00%, RR: 0.62, 95% CI:
0.47–0.83, P 5 .0011), but only after a major protocol change in advanced phases
of the trial. Major bleeding events were higher in the intervention group (0.80%) versus
the control group (0.30%). The Absolute Risk Difference was 0.51 (95% CI 0.12–
0.89).44 The ADOPT trial showed no significant difference in VTE outcomes at
30 days when comparing 30-day apixaban 2.5 mg BID to enoxaparin 40 mg QD for
6 to 14 days (2.70% vs 3.10%, RR: 0.87, 95% CI: 0.62–1.23, P 5 .44), though with
an increased major bleeding risk with apixaban (0.47% vs 0.19%, RR: 2.58, 95%
CI: 1.02–7.24, P5.04).45 The MAGELLAN trial found that extended prophylaxis with
rivaroxaban 10 mg QD reduced VTE at 35 days compared to a 104 day course of
enoxaparin 40 mg QD followed by placebo (4.40% vs 5.70%, RR: 0.77, 95% CI:
0.62–0.96, P 5 .02), but increased clinically relevant bleeding (4.10% vs 1.70%, RR:
2.50, 95% CI: 1.85–3.25, P<.001).46 A subgroup analysis of the trial data excluding
high bleeding risk patients showed improved safety outcomes while maintaining effi-
cacy.27 The APEX trial led to the first DOAC approval for extended VTE prophylaxis.
Betrixaban 80 mg QD for 35 to 42 days was compared to an inpatient 104-day
course of enoxaparin 40 mg QD followed by placebo, demonstrating efficacy in
reducing VTE events in the intervention (6.90% in the betrixaban vs 8.5% in the control

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10 Tsaftaridis et al

Fig. 2. Thrombotic and major bleeding events in the 5 RCTs of extended thromboprophy-
laxis in medically ill patients. aTotal VTE including asymptomatic proximal DVT detected
by ultrasonography, symptomatic VTE, and fatal VTE. bSymptomatic and fatal VTE only.

group, RR: 0.81, 95% CI 0.65–1.00, P5.054), and a favorable safety profile. Of note,
betrixaban is no longer available.17
The MARINER trial compared postdischarge rivaroxaban 10 mg QD with placebo
for up to 45 days in 12,024 medical inpatients. The primary outcome of symptomatic
VTE or VTE-related death was 0.83% versus 1.10% for placebo (hazard ratio 0.76,
95% CI: 0.52–1.09; P 5 .14), however prespecified secondary outcomes showed sig-
nificant reduction in symptomatic VTE (0.18% in the rivaroxaban vs 0.42% in the pla-
cebo group; HR 0.44, 95% CI: 0.22–0.89) and symptomatic VTE and all-cause
mortality (1.30% vs 1.78% respectively, HR 0.73, 95% CI: 0.54–0.97). The risk of major
bleeding was very low in both groups: 0.28% in the rivaroxaban vs 0.15% in the con-
trol group (HR: 1.88, 95% CI: 0.84 to 4.23).43 Additional prespecified secondary out-
comes also showed a 28% significant reduction in major thromboembolism (1.77% vs
1.28%, 95% CI: 0.52–1.00; P 5 .049) that included arterial thromboembolism and car-
diovascular death with extended thromboprophylaxis.47

Risk-benefit balance
A meta-analysis of the 5 aforementioned clinical trials concluded that extended-
duration VTE prophylaxis reduced symptomatic VTE or VTE-related death compared
with standard of care (0.80% vs 1.20%; RR: 0.61, 95% CI: 0.44–0.83; P 5 .002) but
with an increased risk of major or fatal bleeding (0.60% vs 0.30%; RR: 2.04, 95%
CI: 1.42–2.91; P<.001).48 However, in defined low-bleed risk populations that
excluded 5 key major bleed risk factors (active cancer, dual antiplatelet therapy at
hospitalization, a recent history of bleeding or active gastroduodenal ulcer within
3 months before hospitalization, or history bronchiectasis or pulmonary cavitation),
a strategy of extended thromboprophylaxis had net clinical benefit across all major
cardiovascular endpoints (both arterial and venous thromboembolism) with a

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 Medical Inpatient Venous Thromboembolism Prevention 11

Fig. 3. Inpatient and extended postdischarge thromboprophylaxis algorithm. aBased on

overall VTE risk factor profile (see Table 1), bBased on overall bleeding risk factor profile
(Table 3), cStudied in randomized controlled trials (RCTs) with inpatient stays from 6-
14 days (see Fig. 1).46,52

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12 Tsaftaridis et al

number-needed-to-treat of 55 and a number-needed-to-harm of 560, a 10:1 ratio.27,49

Lastly the net clinical benefit of extended thromboprophylaxis appeared more robust
the longer a patient is receiving thromboprophylaxis across the 45 days
postdischarge.49
Mechanical Thromboprophylaxis
Options for mechanical VTE prophylaxis for patients at high-bleed risk include inter-
mittent pneumatic compression devices (IPC), graduated compression stockings
(GCS), and venous foot pumps. Limited data exists comparing the effectiveness of
these 3 different modalities in the hospitalized medically ill patient. A systematic review
examined 10 head-to-head comparisons of IPC and GCS.50 Nine of the 10 studies
were in surgical patients. Only 3 of the studies showed IPC to have a lower rate of
VTE compared to GCS. The crude DVT rate was 5.90% for GCS and 2.80% for
IPC.50 In the CLOTS 1 and 2 randomized trials that compared GCS to no intervention
in stroke patients; there was no statistically significant difference in terms of thrombo-
embolic events or other outcomes, including mortality.51
Thromboprophylaxis Algorithm (Inpatient and Postdischarge)
A suggested VTE risk stratification algorithm for appropriate inpatient and extended
postdischarge thromboprophylaxis based on the latest evidence and guideline rec-
ommendations is shown in Fig. 3.
The role of clinical decision support in evidence-based thromboprophylaxis
The complexity and need for individualized thromboprophylaxis in this population may
contribute to low adoption of evidence-based practice. Systematic strategies of
improving outcomes for medical inpatients include national prevention programs,
audit strategies, dedicated staff for VTE prevention, electronic alerts, preprinted
thromboprophylaxis orders and most recently active clinical decision support tools.
Most interventions have shown mixed results in terms of improving appropriate throm-
boprophylaxis—rates of thromboprophylaxis conformant to guideline recommenda-
tions—and hard outcomes (VTE and related morbidity and mortality).53 Active
clinical decision support tools, especially ones that can be implemented into any elec-
tronic health record (EHR) appear the most promising, especially if built to be portable
between different health care systems and information technology infrastructures.53 A
recent large cluster randomized trial using an EHR-agnostic platform and incorpo-
rating the IMPROVE-DD VTE RAM in hospitalized medical patients showed a 52%
relative increase in appropriate inpatient and a 93% relative increase in appropriate
at-discharge extended thromboprophylaxis, with a 29% decrease in major thrombo-
embolism and no excess major bleeding.54 The effectiveness of the intervention in
increasing appropriate postdischarge thromboprophylaxis was preserved in patients
with COVID-19, given that inpatient thromboprophylaxis was increased due to
increased vigilance in this patient population.55 The most recent antithrombotic guide-
lines from the International Union of Angiology recommend health informatics technol-
ogy in the form of electronic alerts or clinical decision support tools to identify key
populations that may benefit from pharmacologic thromboprophylaxis, based on
moderate level of evidence.10

SUMMARY

VTE is the third most common vascular disease globally and hospitalized medical pa-
tients represent 22% of all VTE events. VTE risk in hospitalized medical patients is
influenced by patient-specific, and acute illness-related factors, including age more

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 Medical Inpatient Venous Thromboembolism Prevention 13

than 75 years, history of VTE, acute infection, and active malignancy. Validated and
guideline-endorsed RAMs like PADUA, IMPROVE, and IMPROVE-DD help identify pa-
tients at elevated risk for VTE. Bleeding risk assessment is also important for deter-
mining the net clinical benefit when considering pharmacologic thromboprophylaxis,
and IMPROVE BLEED is the only extensively validated RAM for this population. Land-
mark clinical trials have established LMWH as effective in reducing VTE during the
inpatient period. Given that the risk of VTE can extend up to 45 days from hospital
discharge, several randomized controlled trials have studied extended thrombopro-
phylaxis in hospitalized medically patients. In defined populations at high VTE and
low-bleed risk, extended thromboprophylaxis with a DOAC (rivaroxaban) shows net
clinical benefit. Active, EHR-integrated clinical decision support tools have the poten-
tial to improve outcomes.

FUTURE DEVELOPMENTS

Ongoing phase II and III clinical trials are assessing the efficacy and safety of factor XI/
XIa inhibitor medications, given patients with lower factor XI levels show lower rates of
VTE and ischemic stroke, but no associated increase in major bleeding.56 These
agents have potential to optimize net clinical benefit in high VTE risk populations
such as hospitalized medical patients that are also at increased bleed risk.

CLINICS CARE POINTS

 Select medical inpatients are at risk of venous thromboembolism (VTE) in the inpatient
setting and a further select population of high VTE risk patients is at VTE risk up to
45 days postdischarge. Current universal or group-based thromboprophylaxis practice leaves
a large percentage under-prophylaxed or over-prophylaxed. As such, medical inpatients
require an individualized approach to VTE risk assessment.
 Thromboprophylaxis of medical inpatients should be based on an individualized approach to
both VTE risk using either a comprehensive assessment of VTE risk factors (ie, age, active
malignancy, and prior VTE history) or preferably with a validated VTE risk assessment models
(RAM) in addition to an individualized approach to bleeding risk using individual high-bleed
risk factors, that is, anemia, thrombocytopenia, high BMI, gastroduodenal ulcers,
rehospitalization), or a RAM for bleeding.
 For inpatients deemed at elevated risk for VTE (ie, Padua score of 4 or IMPROVE/IMPROVE-
DD score 2) and without high bleeding risk, pharmacologic prophylaxis should be initiated.
Once daily LMWH is preferred for patients with a creatinine clearance (CrCl) > 30 mL/min,
while twice-daily or thrice-daily unfractionated heparin is recommended for those with a
CrCl lesser than 30 mL/min. For patients with sufficiently high bleeding risk (high individual
bleed risk factors or IMPROVE Bleed 7), consider mechanical VTE prophylaxis.
 A significant proportion of VTE events occur after hospitalization. Extended prophylaxis with
rivaroxaban 10 mg daily until 31 to 39 days postadmission should be considered in patients
with high VTE risk features (age >75 years, or with a history of VTE or cancer, or with an
IMPROVE score 4, or an IMPROVE-DD score 4) and at low bleed risk.
 Integration of active clinical decision support tools within electronic health records can
enhance adherence to evidence-based thromboprophylaxis guidelines, both during
hospitalization and at the time of discharge. Using passive electronic alert systems may be a
reasonable alternative when the infrastructure is not available.

DISCLOSURES

Dr A.C. Spyropoulos reports honoraria from Janssen, Bayer, Bristol Myers Squibb,
Pfizer, and Sanofi and research grants from Janssen and Boehringer Ingelheim, United

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14 Tsaftaridis et al

States. He is also a member of the ATLAS group, an academic research organization.

Dr S. Kaatz reports Osmosis Research (grant), Janssen, United States, (grant), Bristol
Myers Squibb, United States, (grant), NIH, United States, (grant), Janssen (personal
fees), Pfizer/Bristol Myers Squibb (personal fees), Astra Zeneca (personal fees), Phase
Bio (personal fees), Gilead (personal fees), Board of Directors for Anticoagulation
Forum (other), Scientific Advisory Board for National Blood Clot Alliance (other),
PERT Consortium (other). Dr Tsaftaridis is funded by the Broxmeyer Fellowship in Clin-
ical Thrombosis. The other author has nothing to disclose.

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