Enoxaparin Dosing and Anti-Xa Monitoring in Morbidly

Obese Medicine Patients (EDM-MOM)

Vivian (Wint War) Phyo, PharmD, BCPS – PGY2 Internal Medicine Pharmacy Resident
Karishma Deodhar, PharmD, BCPS – Clinical Pharmacist, Internal Medicine
Amy Chang, PharmD, BCPS – Clinical Pharmacist, Internal Medicine

Eskenazi Health, Indianapolis, IN

April 25th, 2024

The authors have no actual or potential conflicts of interest in relation to this presentation
 Enoxaparin in Obesity
VTE risk factors
• Obesity
• Reduced mobility
Pharmacokinetic changes
• Increase in adipose tissue
• Decrease in tissue perfusion
• Increase in creatinine clearance
2012 CHEST guidelines
• Provided anti-Xa goals for monitoring
• No recommendation on enoxaparin dosing for patients with obesity
Yang G, De Staercke C, Hooper WC. Open J Prev Med. 2012;2(4):499-509
VTE: venous thromboembolism Lee YR, et al. Clin Drug Investig. 2020;40(1):33-40
CHEST: The American College of Chest Physicians Garcia DA, et al. Chest. 2012;141(2 Suppl):e24S-e43S
Literature Review
 VTE Prophylaxis
Freeman A, et al. Am J Hematol. 2012;87(7):740-743
Objective Compare 3 enoxaparin dosing regimens for VTE prophylaxis in obese medicine patients
Design Prospective, comparison study
BMI > 40 kg/m2 with > 1 VTE risk factors and CrCl > 30 ml/min
Patient
Mean BMI = 62.1 kg/m2 (range: 40.5-82.4)
Characteristics
Mean weight = 176 kg (range: 115-256)
Fixed dose (FD): Enoxaparin 40mg subcutaneously daily (n=11)
Intervention Low dose (LD): Enoxaparin 0.4 mg/kg subcutaneously daily (n=9)
High dose (HD): Enoxaparin 0.5 mg/kg subcutaneously daily (n=11)
Goal anti-Xa of 0.2-0.5 units/mL achieved in each group:
- FD: 2/11 (18.2%)
Results - LD: 3/9 (33.3%)
- HD: 10/11 (90.9%)
No difference in the incidence of bleeding, DVT, or HIT
BMI: body mass index CrCl: creatinine clearance
DVT: deep venous thrombosis HIT: heparin-induced thrombocytopenia
 VTE Treatment
Curry MA, et al. Ann Pharmacother. 2019;53(6):567-573
Evaluate if reduced dose enoxaparin was more effective than standard dose at achieving goal
Objective
anti-Xa levels in morbidly obese patients
Design Prospective, randomized controlled study
BMI > 40 kg/m2 and CrCl > 30 ml/min
Patient
Mean BMI = 46.7 kg/m2 (IQR: 42.7-54.9)
Characteristics
Mean weight = 147 kg (IQR: 102-271.9)
Reduced dose: Enoxaparin 0.8 mg/kg subcutaneously Q12H (n=28)
Intervention
Standard dose: Enoxaparin 1 mg/kg subcutaneously Q12H (n=26)
Reduced dose (n=28) Standard dose (n=26) p value
Initial enoxaparin dose, median (IQR) 120 mg (110-140) 150 mg (130-160) 0.0001
Results Initial anti-Xa:
At goal (0.5-1.1 units/mL) 25 (89.3%) 20 (76.9%) 0.29
Supratherapeutic 1 (3.6%) 6 (33.1%)
Subtherapeutic 2 (7.1%) 0
IQR: interquartile range
Self-Assessment Question #1
Which of the following statements accurately represents the
gap(s) in current literature surrounding enoxaparin use in
morbidly obese medicine patients?
a) Optimal dosing strategy is not well-defined
b) Optimal dosing is 40 mg daily for VTE prophylaxis
c) Optimal dosing is 2 mg/kg/day divided Q12H for VTE treatment
d) Large number of studies with large sample sizes
Gaps in Current Literature
Small sample sizes for obese
medicine patients

Various dosing strategies utilized

Optimal dosing strategy unclear

for various BMI ranges
 Enoxaparin Dosing and Anti-Xa Monitoring in
Morbidly Obese Medicine Patients (EDM-MOM)
Eskenazi
Health

333-bed, tertiary
care, safety net
hospital located in
Indianapolis, IN
Study Design
• Single-center, retrospective, observational study
(Institutional Review Board approved)
• Study period: January 2018 – July 2023

Purpose: Evaluate the efficacy of the

current enoxaparin dosing protocols
based on anti-Xa levels in acutely ill,
morbidly obese medical patients
 Eskenazi Enoxaparin Protocol
For medicine patients with weight > 120 kg or BMI > 40 kg/m2

Prophylaxis
• 0.5 mg/kg/day* divided Q12H

Anti-Xa NOT at goal

• Goal anti-Xa: 0.2 – 0.4 units/mL
Dose
adjustment
Treatment
up to + 20%*
• BMI 40-49: 0.9 mg/kg Q12H*
• BMI > 50: 0.75 mg/kg Q12H*
• Goal anti-Xa: 0.5 – 1 units/mL
*Rounded to the nearest available syringe size
Eligibility Criteria
Inclusion
• Age > 18 years
• Weight > 120 kg or
BMI > 40 kg/m2
• Admitted to medicine primary
team
• > 1 anti-Xa level drawn 3-5
hours after at least 3
consecutive, consistent doses
of enoxaparin
Exclusion
• Baseline CrCl < 30 ml/min using
Cockcroft-Gault equation on
adjusted body weight
• Pregnant patients
• > 10 kg weight difference while
on enoxaparin (e.g.,
decompensated heart failure
after aggressive diuresis,
documentation of weight
change without clear reasons)
Self-Assessment Question #2
Which of the following condition(s) need to be met to be
included in this study?
a) Patients must have received at least 3 consecutive, consistent
doses of enoxaparin
b) Anti-Xa level drawn 6-8 hours after the first dose
c) Anti-Xa level drawn 3-5 hours after the third dose
d) Both A & C
 Primary Outcomes
• Percentage of initial anti-Xa levels within goal ranges
• Comparison of median dose (in mg/kg/day) between those within
goal and those not within goal anti-Xa

BMI < 40 kg/m2 BMI BMI BMI

TBW > 120 kg 40-49 kg/m2 50-59 kg/m2 > 60 kg/m2
TBW: total body weight
 Secondary Outcomes
• Percentage of subtherapeutic and supratherapeutic initial anti-Xa levels
• Clinically significant bleeding while on enoxaparin
• Decrease in hemoglobin level of > 2 g/dL or documented transfusion of > 2 units
of packed red blood cells
• Incidence of new thromboembolic events during admission
• Confirmed by positive doppler ultrasonography, chest CT, and/or CT pulmonary
angiogram

BMI < 40 kg/m2 BMI BMI BMI

TBW > 120 kg 40-49 kg/m2 50-59 kg/m2 > 60 kg/m2
CT: computed tomography
VTE Prophylaxis Results
 Prophylaxis: Baseline Characteristics
All patients BMI < 40 kg/m2, BMI 40-49 kg/m2 BMI 50-59 kg/m2 BMI > 60 kg/m2
Characteristics
(N=217) TBW > 120 kg (n=7) (n=97) (n=61) (n=52)
Age, years 52 (42-62) 56 (46-76) 54 (45-63) 55 (44-62) 46 (36-56)
Female sex* 102 (47) 0 45 (46.4) 32 (52.5) 25 (48.1)
TBW, kg 146 (127-173) 130 (121-138) 128 (110-143) 155 (142-174) 194 (173-220)
BMI, kg/m2 50 (43-59) 39 (37-39) 43 (42-46) 54 (51-57) 68 (63-74)
SCr, mg/dL 0.86 (0.68-1.08) 0.86 (0.52-0.92) 0.89 (0.65-1.13) 0.82 (0.69-1.15) 0.87 (0.71-1.0)
CrCl, ml/min 120 (92.5-120) 120 116 (88.5-120) 120 (85-120) 120 (108-120)
Concomitant antiplatelet* 55 (25.3) 7 (100) 25 (25.8) 16 (26.2) 14 (26.9)
None* 162 (74.7) 0 72 (74.2) 45 (73.8) 38 (73.0)
Aspirin* 53 (24.4) 0 25 (25.8) 15 (24.6) 14 (26.9)
Clopidogrel* 6 (2.8) 0 3 (3.1) 3 (4.9) 0
Data represented as median (IQR) unless otherwise stated
*Represented as No. (%)

SCr: serum creatinine

 Prophylaxis: Initial Anti-Xa

Percentage of initial anti-Xa levels within goal ranges

All patients BMI < 40 kg/m2, BMI 40-49 kg/m2 BMI 50-59 kg/m2 BMI > 60 kg/m2
Initial Anti-Xa
(N=217) TBW > 120 kg (n=7) (n=97) (n=61) (n=52)
Sub-prophylactic (< 0.2 units/mL) 134 (61.8) 5 (71.4) 57 (58.8) 42 (68.9) 30 (57.7)
Goal (0.2-0.4 units/mL) 76 (35.0) 1 (14.3) 38 (39.2) 16 (26.2) 21 (40.4)
Supra-prophylactic (> 0.4 units/mL) 7 (3.2) 1 (14.3) 2 (2.0) 3 (4.9) 1 (1.9)
Data represented as No. (%) unless otherwise stated
 Prophylaxis: Median Dose
Comparison of median dose between those within goal and those
not within goal anti-Xa
Patient Groups Anti-Xa within goal Anti-Xa NOT within goal p value
n 118 99
All patients (N=217) <0.001
Dose* 0.57 (0.51-0.64) 0.5 (0.44-0.56)
BMI < 40 kg/m2, n 2 5
0.846
TBW > 120 kg (n=7) Dose* 0.61 0.61 (0.52-0.64)
n 56 41
BMI 40-49 kg/m2 (n=97) <0.001
Dose* 0.62 (0.54-0.71) 0.52 (0.47-0.58)
n 31 30
BMI 50-59 kg/m2 (n=61) 0.008
Dose* 0.56 (0.48-0.64) 0.50 (0.44-0.55)
n 29 23
BMI > 60 kg/m2 (n=52) <0.001
Dose* 0.55 (0.50-0.58) 0.46 (0.39-0.49)
Data represented as median (IQR) unless otherwise stated
*Last dosing regimen (in mg/kg/day) patient was on before discharge or enoxaparin was discontinued
 Prophylaxis: Secondary Outcomes

BMI < 40 kg/m2, BMI 40-49 kg/m2 BMI 50-59 kg/m2 BMI > 60 kg/m2
Safety Endpoints
TBW > 120 kg (n=7) (n=97) (n=61) (n=52)
Bleeding
Hemoglobin Drop 5 (71.4) 39 (40.2) 18 (29.5) 7 (13.5)
Blood Transfusion 0 9 (9.3) 6 (9.8) 0
Anti-Xa? - 1 subtherapeutic 1 supratherapeutic -
Anti-platelet? - 3 aspirin 2 aspirin -
Thrombotic Events 0 5 (5.1) 1 (1.6) 1 (1.9)
Anti-Xa? - 1 subtherapeutic at goal -
COVID? - 3 (60) 1 (100) 0
Data represented as No. (%) unless otherwise stated
VTE Treatment Results
 Treatment: Baseline Characteristics
All patients BMI < 40 kg/m2, BMI 40-49 kg/m2 BMI 50-59 kg/m2 BMI > 60 kg/m2
Characteristics
(N=30) TBW > 120 kg (n=1) (n=13) (n=11) (n=5)
Age, years 60 (50-64) 54 53 (41-64) 63 (50-69) 60 (54-67)
Female sex* 16 (53.3) 0 7 (53.8) 7 (63.6) 2 (40)
TBW, kg 146 (126-169) 122 131 (120-152) 147 (137-170) 200 (174-253)
BMI, kg/m2 51 (45-55) 36 45 (43-47) 54 (51-55) 64 (60-80)
SCr, mg/dL 0.96 (0.77-1.21) 1.26 0.9 (0.76-1.19) 1.13 (0.77-1.53) 0.9 (0.74-0.96)
CrCl, ml/min 111 (77-120) 90 111 (75-120) 87 (50-120) 120 (105-120)
Concomitant antiplatelet* 8 (26.6) 1 2 (15.4) 3 (27.3) 2 (40)
None* 22 (73.3) - 11 (84.6) 8 (72.7) 3 (60)
Aspirin* 7 (23.3) 1 2 (15.4) 2 (18.2) 2 (40)
Clopidogrel* 1 (3.3) 0 0 1 (9.0) 0
Warfarin* 10 (33.3) 0 2 (15.4) 5 (45.4) 3 (60)
Data represented as median (IQR) unless otherwise stated
*Represented as No. (%)
 Treatment: Initial Anti-Xa

Percentage of initial anti-Xa levels within goal ranges

All patients BMI < 40 kg/m2, BMI 40-49 kg/m2 BMI 50-59 kg/m2 BMI > 60 kg/m2
Initial Anti-Xa
(N=30) TBW > 120 kg (n=1) (n=13) (n=11) (n=5)
Subtherapeutic (< 0.5 units/mL) 1 (3.3) - 1 (7.7) 0 0
Goal (0.5-1 units/mL) 18 (60) - 8 (61.5) 7 (63.6) 3 (60)
Supratherapeutic (> 1 units/mL) 11 (36.6) 1 4 (30.8) 4 (36.3) 2 (40)
Data represented as No. (%) unless otherwise stated
 Treatment: Primary Outcome
Comparison of median dose between those within goal and those
not within goal anti-Xa
Patient Groups Anti-Xa within goal Anti-Xa NOT within goal p value
n 19 11
All patients (N=30) 0.085
Dose* 1.63 (1.46-1.93) 1.90 (1.78-1.97)
BMI < 40 kg/m2, n - 1
-
TBW > 120 kg (n=1) Dose* - 2
n 9 4
BMI 40-49 kg/m2 (n=13) 0.938
Dose* 1.93 (1.72-1.99) 1.90 (1.87-1.98)
n 7 4
BMI 50-59 kg/m2 (n=11) 0.219
Dose* 1.48 (1.29-1.63) 1.88 (1.41-2.04)
n 3 2
BMI > 60 kg/m2 (n=5) 0.149
Dose* 1.48 (0.99-1.5) 1.74
Data represented as median (IQR) unless otherwise stated
*Last dosing regimen (in mg/kg/day) patient was on before discharge or enoxaparin was discontinued
 Treatment: Secondary Outcomes

BMI < 40 kg/m2, BMI 40-49 kg/m2 BMI 50-59 kg/m2 BMI > 60 kg/m2
Safety Endpoints
TBW > 120 kg (n=1) (n=13) (n=11) (n=5)
Bleeding
Hemoglobin Drop 1 3 3 1
Blood Transfusion 1 1 0 0
Anti-Xa? 1 supratherapeutic at goal - -
Anti-platelet? 1 aspirin 0 - -
Data represented as No. (%) unless otherwise stated
 Strengths and Limitations
Strengths

- Single center - Large sample size for VTE

- Reliance on documentation prophylaxis
- Lack data for COVID-19 - Focus on medicine patients
status, mechanical prophylaxis with obesity
methods, and Padua score - All outcomes stratified by BMI
- Limited applicability of ranges
bleeding and thromboembolic
events

Limitations
- Anti-Xa as surrogate for
clinical outcomes
Conclusions
Mean enoxaparin dose of 0.5 mg/kg/day
resulted in sub-prophylactic initial anti-Xa levels
in 61.8% of all obese patients

Across all BMI ranges, obese patients required

enoxaparin doses closer to 0.6 mg/kg/day to
achieve prophylactic goal anti-Xa range

Less than standard enoxaparin dose (1 mg/kg

Q12H) was needed to achieve therapeutic goal
anti-Xa levels in patients with higher BMI
 Future Directions

VTE prophylaxis protocol change Potential research idea

• Increase initial dose from 0.5 to 0.6 • Analyze differences between pre- and
mg/kg/day divided Q12H for obese post-protocol change
medicine patients
 Acknowledgments
• Karishma Deodhar, PharmD, BCPS
• Amy Chang, PharmD, BCPS
• Mary Blair, PharmD, BCPS, BCCCP
• Allison Boyd, PharmD, BCCCP
• Christopher Geik, PharmD, BCPS
 References
1. Yang G, De Staercke C, Hooper WC. The effects of obesity on venous
thromboembolism: A review. Open J Prev Med. 2012;2(4):499-509
2. Lee YR, Palmere PJ, Burton CE, Benavides TM. Stratifying Therapeutic Enoxaparin Dose
in Morbidly Obese Patients by BMI Class: A Retrospective Cohort Study. Clin Drug
Investig. 2020;40(1):33-40
3. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e24S-e43S
4. Freeman A, Horner T, Pendleton RC, Rondina MT. Prospective comparison of three
enoxaparin dosing regimens to achieve target anti-factor Xa levels in hospitalized,
medically ill patients with extreme obesity. Am J Hematol. 2012;87(7):740-743
5. Curry MA, LaFollette JA, Alexander BR, Evans KS, Tran RH, Kempton CL. Evaluation of
Treatment-Dose Enoxaparin in Acutely Ill Morbidly Obese Patients at an Academic
Medical Center: A Randomized Clinical Trial. Ann Pharmacother. 2019;53(6):567-573
Enoxaparin Dosing and Anti-Xa Monitoring in Morbidly
Obese Medicine Patients (EDM-MOM)
Vivian (Wint War) Phyo, PharmD, BCPS – PGY2 Internal Medicine Pharmacy Resident
Karishma Deodhar, PharmD, BCPS – Clinical Pharmacist, Internal Medicine
Amy Chang, PharmD, BCPS – Clinical Pharmacist, Internal Medicine

Eskenazi Health, Indianapolis, IN

April 25th, 2024

The authors have no actual or potential conflicts of interest in relation to this presentation