This randomized controlled trial compared the efficacy of enoxaparin versus placebo for preventing symptomatic venous thromboembolism in 2559 hospitalized older adult medical patients. The primary outcome of symptomatic deep vein thrombosis, pulmonary embolism or fatal pulmonary embolism within 30 days occurred in 1.8% of patients receiving enoxaparin and 2.2% of patients receiving placebo, showing no significant difference. Secondary outcomes including events up to 90 days also showed no significant differences in efficacy or safety between the groups. The results do not support the routine use of enoxaparin for thromboprophylaxis in this population.

1. Enoxaparin versus Placebo to Prevent
Symptomatic Venous Thromboembolism in
Hospitalized Older Adult Medical Patients
Dominique Mottier, M.D.,1 Philippe Girard, M.D.,2 Francis Couturaud, M.D., Ph.D.,1 Karine Lacut, M.D., Ph.D.,1
Emmanuelle Le Moigne, M.D., Ph.D.,1 Nicolas Paleiron, M.D.,3 Dewi Guellec, M.D.,4 Olivier Sanchez, M.D., Ph.D.,5
Virginie Cogulet, Pharm.D.,6 Silvy Laporte, Ph.D.,7 Gisele Marhic,8 Patrick Mismetti, M.D., Ph.D.,9 Emilie Presles, M.Sc.,7
Helia Robert-Ebadi, M.D.,10 Isabelle Mahe, M.D., Ph.D.,11 Ludovic Plaisance, M.D.,12 Jean-Luc Reny, M.D., Ph.D.,13
Pauline Darbellay Farhoumand, M.D.,13 Clemence Cuvelier, M.D.,13 Catherine Le Henaff, M.D.,14 Yannick Lambert, M.D.,14
Marc Danguy des Deserts, M.D.,15 Claire Rousseau Legrand, M.D.,16 Sebastien Boutreux, M.D.,17 Yves Bleher, M.D.,18
Romain Decours, M.D.,19 Albert Trinh-Duc, M.D.,20 Guillaume Armengol, M.D.,21 Ygal Benhamou, M.D., Ph.D.,21
Aurelie Daumas, M.D., Ph.D.,22 Sarah-Lou Guyot, M.D.,23 Hugo De Carvalho, M.D.,23 Bouchra Lamia, M.D., M.P.H., Ph.D.,24
Marc Righini, M.D.,10 Guy Meyer, M.D., Ph.D.,5 and Gregoire Le Gal, M.D., Ph.D.25
BY DR SHISHIR KUMAR
FACULTY IN CHARGE: DR AMIT KUMAR SHARMA
SENIOR RESIDENT: DR ASHISH KUMAR SINGH

2. AIM
To compare the efficacy of Enoxaparin to Placebo in preventing
symptomatic thromboembolism in hospitalized older adult medical
patients with an acute medical illness.

3. ● Admission to the hospital is a major risk factor for the development of venous
thromboembolism (VTE).
● Making VTE prevention in hospitalized patients a potentially important
strategy to reduce the global VTE burden.
● Whether thromboprophylaxis with low-molecular-weight heparin prevents
symptomatic VTE in medically ill, hospitalized older adults remains debated.
● MEDENOX trial (MEDical patients with ENOXaparin) and others,
demonstrated efficacy of low-molecular-weight heparin in reducing outcome
of symptomatic and asymptomatic VTE events among patients 40 years of
age or older hospitalized with acute medical conditions.
BACKGROUND

4. BACKGROUND
● In these trials, asymptomatic VTE accounted for the vast majority of events.
● Publication of the results from these trials led to the widespread
implementation of thromboprophylaxis in hospitals.
● Notably, clinical trials using direct oral anticoagulants did not demonstrate a
favorable risk–benefit profile compared with low-molecular-weight heparin in
medical thromboprophylaxis
● Thus direct oral anticoagulants are not commonly used for prophylaxis.

5. METHODOLOGY
● Name of the study: SYMPTOMS (Systematic elderly Medical Patients Thromboprophylaxis:
Efficacy on Symptomatic OutcoMeS)
● Study design:
○ Prospective Randomised placebo controlled parallel group
○ double blind
● Place of study: Multicentric and multinational - done at 47 sites in France and
Switzerland
● Sample size: 2559 (expected 5030)
● Total study duration: 3 years (inclusion period) + 3 months (followup)
● Published on : June 27, 2023

6. Inclusion criteria
● Patients 70 years of age or older
● admitted to the hospital for an acute medical illness
● anticipated duration of hospitalization of at least 4 days
● life expectancy of at least 3 months
Inclusion was not restricted based on patients’ mobility, thrombotic risk factors, or
admitting medical conditions.

7. Exclusion criteria
• Admission for one of the following reasons:
o Planned medical procedure.
o Routine health assessment requiring admission (e.g., routine colonoscopy).
o Admission encountered for another life circumstance that causes no
bearing on health status and requires no medical intervention (e.g., lack of
housing, economic inadequacy, caregiver respite, family circumstances,
administrative).
• Hypersensitivity to heparin
• History of Heparin Induced Thrombocytopenia
• Active bleeding
• Bacterial endocarditis
• Platelet count of less than 80,000 per cubic millimeter

8. Exclusion criteria
• Patients who require anticoagulant therapy for any indication, and those who
received any type of anticoagulant therapy for > 48 hours
• Organic lesion prone to bleeding.
• Hemorrhagic events or bleeding tendency due to hemostasis disorders.
• Concomitant use of aspirin (> 160 mg/day), clopidogrel (> 75 mg/day), or of
combined antiplatelet therapy
• Creatinine clearance < 15 ml/min
• Unable or unwilling to consent
• Ischemic stroke + hemorrhagic transformation

9. Certain criteria were changed
● Min age reduced from 75 to 70
● Minimum platelet count changed from 80,000 to 1 lakh

10. Intervention
● Patients were randomly assigned in a 1:1 ratio to receive a subcutaneous
injection of either 40mg of enoxaparin or placebo in 0.4ml prefilled syringes
administered daily for 10+- 4 days.
● Min of 6 and max 14 inj administered.
● Pt were followed up after discharge after 30 days and 90 days respectively.
● At each contact, patients were asked about visits to the hospital or to a
physician, changes in medications, and diagnostic tests.
● In case of a suspected outcome event, an adjudication package containing all
relevant information was submitted to the independent clinical events
committee.

11. Randomization and blinding
● Randomization was centralized using a web based interface.
● Method of sequence generation - Computerized random number generator
● Randomization sequence stratified by center, antiplatelet use and creatinine
clearance.
● Trial participants, trial personnel (including trial site pharmacy staff),
investigators, and members of the independent clinical events committee
were blinded to trial group allocation.

12. Trail Flow chart

13. Outcome measures
Primary outcome (occurence of any of the events through day 30 visit)
● Symptomatically confirmed DVT
● Symptomatically confirmed PE
● fatal pulmonary embolism
Secondary outcome
● Symptomatically confirmed VTE on day 90
● Fatal pulmonary embolism through day 90
● Atherothrombotic CardioVascular events at day 30 and day 90
● Death from any cause at day 30 and day 90
● major bleeding at day 30 and day 90

14. STATISTICAL ANALYSIS
● Cumulative incidences were presented with corresponding 95% confidence
intervals.
● p value of less than 0.05 was considered significant.
● Statistical analyses performed using SAS version 9.4 software.
● Figures constructed using R software, version 4.0.2.

15. Patient and trial regimen
● From September 2015 through September 2020, 2559 patients were
randomly assigned to treatment.
● At randomization, characteristics of the two groups were well balanced.
● 1278 patients received enoxaparin and 1263 received placebo.
● median length of stay was 8 days.
● median duration of trial drug administration was 7 days.
RESULT

17. Efficacy outcomes
Primary efficacy outcomes
● occurred in 22 out of 1278 (1.8%) patients in the enoxaparin group and in 27
out of 1263 (2.2%) patients in the placebo group.

18. Efficacy outcomes
Secondary efficacy outcome
● At 90 days, there was 1 percentage point cumulative incidence difference in
the risk of symptomatic VTE events: 25 out of 1278 (2.0%) in the enoxaparin
group versus 37 out of 1273 (3.0%) in the placebo group.
● Of these 62 events, 39 were symptomatic pulmonary emboli (14 and 25 in
the enoxaparin and placebo groups, respectively).
● Hospital readmission and/or death occurred due to pulmonary embolism (5
deaths in the enoxaparin and 11 deaths in the placebo group) .
● Risk of atherosclerotic cardiovascular events and the risk of death from any
cause at 30 days was similar between the two groups.

19. Efficacy outcomes

20. Safety outcomes
● Of major bleeding at 30 days occurred in 11 out of 1278 (0.9%) patients
in the enoxaparin group and in 12 out of 1263 (1.0%) patients in the
placebo group.
● no significant difference between the two groups at 30 days and 90 days
○ clinically relevant non major bleeding,
○ the combination of major and clinically relevant non major bleeding,
○ in fatal bleeding

21. Safety outcomes

22. Kaplan–Meier Cumulative Event Rate for the Primary
Outcome, Symptomatic Venous Thromboembolism at 30
Days

23. DISCUSSION
● No benefit of 40 mg of enoxaparin daily for 6 to 14 days over placebo on the
primary outcome of symptomatic deep vein thrombosis or nonfatal or fatal
pulmonary embolism at 30 days.
● Incidence of major bleeding was not different from the groups.
● In comparison to MEDENOX trial, SYMPTOMS trial
○ Included only symptomatic events in primary outcome
○ Included acutely ill patients regardless of any specific diagnosis, level of immobility, or other
risk factors.
○ Included only older adult patients.

24. DISCUSSION
● Strengths of the trial:
○ Large sample size
○ Robust study design
● Main limitation of the trial:
○ Premature discontinuation
○ Leading to decreased statistical power

25. Future Prospects
● Larger trials needed to know whether thromboprophylaxis provides clinical
benefit.
● Positive results would help patients, physicians and institutions to strengthen
hospital thromboprophylaxis policies.
● Negative results will lead to great cost savings for the health systems
worldwide.

26. THANK YOU