Clinical trial NCT01798550
Conditions: Obesity
Keywords: Enoxaparin dosing Obesity
Sponsor: Emory University
Start date: 2013-03-01; Completion date: 2016-10-15
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine an effective enoxaparin dosing strategy in medically ill, morbidly obese patients. This study will include adult patients greater than 18 yrs of age being admitted to Grady Hospital in Atlanta, GA. Potentially vulnerable patients such as prisoners, children, and pregnant women will not be enrolled in the study. Study participants will be contacted in person by the study personnel once inclusion criteria are met. Written informed consent will be obtained in person while hospitalized. Once the patient is consented they will be given enoxaparin and blood samples will be drawn. The data collected will be from the electronic medical record which is accessed only with a username and password so it is not publicly available. The data will be identifiable upon collection and will be kept on a password protected file on a computer in a locked office. The data will be de-identified after data analysis and only the study personnel will have access to the code that links identifiers to subjects. A HIPAA waiver will be requested to access existing data in order to identify patients for enrollment. All data will be collected in an office in the hospital. The study participants' burden will be minimal and dependent only on time of consent process since morbidly obese patients would be receiving this blood sample collection regardless of their participation in the study.

Detailed description:

Arms: arm 1: Enoxaparin 0.8 mg/kg (using total body weight) twice daily arm 2: Enoxaparin 1 mg/kg (using total body weight) twice daily
Interventions: intervention 1: Enoxaparin
Intervention descriptions: intervention 1: Twice daily dosing

Protocol documents:
Prot_SAP_000.pdf: 
Evaluation of Enoxaparin Dosing in Hospitalized Morbidly 
Obese Patients at an Academic Medical Center 
 
Principle Investigator 
Christine Kempton, MD, MSc 
 
Version November 27th 2012 
 
NCT01798550 
 
 


Evaluation of Enoxaparin Dosing in Hospitalized Morbidly 
Obese Patients at an Academic Medical Center 
 
Principle Investigator 
Christine Kempton, MD, MSc 
Assistant Professor, Department of Pediatrics and Department of Hematology/Oncology 
Associate Clinical Director, Hemostasis and Thrombosis Program 
Clinical Director, Adult Hemophilia Program 
Winship Cancer Institute 
Emory School of Medicine 
 
Study Coordinator 
Brianna Franklin, PharmD 
PGY2 Internal Medicine Pharmacy Resident 
Department of Pharmacy and Drug Information 
Grady Health System 
 
Co-Investigator 
Marjorie Curry, PharmD, BCOP  
Clinical Pharmacist Specialist, Hematology/Oncology 
Georgia Cancer Center for Excellence 
Department of Pharmacy and Drug Information 
Grady Health System 
 
Co-Investigator 
Jennifer LaFollette, PharmD, BCOP  
Clinical Pharmacist Specialist, Hematology/Oncology 
Georgia Cancer Center for Excellence 
Department of Pharmacy and Drug Information 
Grady Health System 
 
 
 
 
 
November 27th 2012 
 
 
 
 
 
 
 
 
 
 
 
 


 
1. Background 
Over the past 20 years, there has been a dramatic increase in the rates of obesity in the United 
States.  The US National Institutes of Health defines obesity as a body mass index (BMI) of ≥30-
39.9 kg/m2 and morbid obesity as a BMI of ≥ 40 kg/m2, using height and weight to obtain BMI. 
According to data published by the US Department of Health and Human Services, over 35 
percent of Americans were considered obese in 2009-2010.1 Obese patients are at increased risk 
for cardiovascular and venous thromboembolic events due to associated comorbidities including 
hyperlipidemia, glucose intolerance, hypertension, and a sedentary lifestyle.2 Treatment of 
cardiovascular and venous thromboembolic events often includes anticoagulation with low 
molecular weight heparin. Thus, there are a significant number of obese patients that will need 
therapeutic anticoagulation.  
 
Landmark clinical trials that led to the approval of the low molecular weight heparin, enoxaparin, 
for treatment of venous thromboembolism and acute coronary syndromes did not list obesity as 
an exclusion criterion, but little data is available on the outcomes in this population due to 
underrepresentation in those trials.3 Data on the safety and efficacy of enoxaparin in the obese 
population is derived mainly from observational or pharmacokinetic studies.4 The implications of 
limited data can be very serious since appropriate dosing is crucial to ensure efficacy and to 
prevent adverse events including bleeding complications.  
 
After low molecular weight heparin is administered, it predominantly concentrates in the plasma 
and highly vascular tissues with little distribution into fat tissue. Since dosing is based on weight, 
obese patients may receive higher doses; however, because there is low distribution into fat 
tissue this may result in elevated anti-Xa levels and thus they can be easily overdosed. It has 
been shown that anti-Xa activity is increased appropriately when the drug is administered to 
patients based on total body weight up to 144 kg.5  The American College of Chest Physicians 
Evidence-based clinical practice guidelines recommend monitoring of anti-Xa levels in obese 
patients.6 Enoxaparin has both anti-Xa and anti-IIa activity however, because of the higher anti-
Xa:IIa ratio, anti-Xa levels are used as a marker of activity.7 It has been suggested that the 
incidence of bleeding is increased when anti-Xa levels are elevated; however, data are 
conflicting.6 
 
There is limited data available to guide dosing of patients above 150 kg. The largest prefilled 
syringe is 150 mg and has resulted in many clinicians capping the dose at 150 mg.4 A 
pharmacokinetic study in 48 healthy obese volunteers (BMI 30-40 kg/m2) at a single study center 
showed that dosing based on total body weight achieved similar maximum anti-Xa levels in both 
obese and non-obese patients, 1.563 IU/ml and 1.488 IU/ml respectively. The authors 
recommended no need to modify dosing in obese patients; however, this trial used 1.5 mg/kg 
daily, included healthy volunteers, and the highest weight studied was only 144 kg.5 A 
prospective study in hospitalized patients with a BMI>30 kg/m2 evaluated anti-Xa levels using 1 
mg/kg twice daily.8 Forty five percent of patients achieved a therapeutic anti-Xa level with the 
mean being 1.17 IU/ml. There was no difference in anti-Xa levels between those with and 
without bleeding episodes. The authors concluded no dose adjustment necessary in this study. 
The results from the above studies suggest standard dosing produces similar ant-Xa levels in 
non-obese and obese patients above 30 kg/m2.  
 
A retrospective study evaluating the dosing of enoxaparin in 26 morbidly obese hospitalized 
patients (BMI ≥40 kg/m2) also evaluated anti-Xa levels.9 A median dose of 0.8 mg/kg based on 
total body weight was utilized with maximum doses up to 150 mg. Forty six percent of patients 
achieved a goal anti-Xa level and 38% of patients were above the anti-Xa goal. The weight cut-
off of 150 kg did not result in statistically significant differences in mean anti-Xa levels (1.12 
IU/ml in patients over 150 kg vs 0.81 IU/ml in patients over 150 kg, p>0.05). Even though 4 out 


of 10 patients with a supratherapeutic anti-Xa level experienced more bleeding events, these 
patients were noted to have additional risk factors for bleeding. This trial suggests that lower 
initial dosing of enoxaparin could be utilized in the morbidly obese population since the majority 
of anti-Xa levels were at or above goal.   
 
There are a few studies looking at clinical outcomes that may be influenced by the dosing 
dilemma of enoxaparin in obesity.  A subgroup analysis of the SYNERGY trial evaluated if BMI 
affected outcomes in hospitalized NSTEMI patients.10 Patients at both extremes of weight were 
dosed with enoxaparin 1mg/kg based on total body weight with no capping of doses. Major 
bleeding, using the TIMI definition, during hospitalization was lower for patients with a BMI 
above 35 compared to those with a BMI below 20 (8.8% vs. 11.4%). In addition, obesity did not 
have an effect on the efficacy outcomes of mortality or myocardial infarction at 30 days and 6 
months which led authors to conclude those with normal renal function should be dosed with 1 
mg/kg of actual body weight regardless of body weight. However, only 3.5% of patients had a 
BMI>40 kg/m2, thus, more research in that group was recommended. A meta-analysis that 
included hospitalized NSTEMI patients with a BMI>30 kg/m2 also showed no increase in major 
bleeding in obese patients who were dosed based on total body weight.11 In contrast, an 
observational study using the CRUSADE database of hospitalized NSTEMI patients showed an 
increased incidence of non CABG related bleeding in patients weighing >150kg receiving 
standard 0.95-1.05 mg/kg dosing compared to those receiving a lower initial dose of <0.95 
mg/kg (11.4% vs. 6.5%, OR 2.42).3 However, as seen in the previous studies, patients over 150 
kg represented a small portion of the study population (0.92%) therefore more safety data is 
warranted in that group.  
 
The Chest guidelines have recommended a dosing nomogram to adjust low molecular weight 
heparin doses; however, the study used to validate the nomogram was performed in a pediatric 
patient population.12 Even though guidelines suggest monitoring and adjusting doses based on 
anti-Xa levels, little guidance is given on whether the initial dose should be empirically decreased 
to a more conservative dose. One strategy is to start with a lower dose, 0.8 mg/kg, which was 
the average dose used in the retrospective study performed by Deal et al. This study supports 
starting with a more conservative initial dose since 84% of patients were at or above the anti-Xa 
goal.9 
 
Grady Health System is an inner city public hospital that serves a predominantly indigent patient 
population and includes a significant number of obese patients.  Patients admitted to the hospital 
for anticoagulation treatment receive enoxaparin dosed 1 mg/kg twice daily using total body 
weight. Because of the significant obese patient population, clinical pharmacists often assist with 
dosing and monitoring in obese patients, including patients weighing more than 150 kg.    
Currently, there is no standard enoxaparin monitoring protocol and thus anti-Xa levels are 
ordered at the discretion of the physician or per the recommendation of a clinical pharmacist.  
Because of the ever increasing body habitus of the US patient population, there is a great need 
to determine optimal dosing regimens for obese patients in order to ensure therapeutic anti-Xa 
levels and prevent bleeding complications. Since previous studies have shown similar anti-Xa 
levels in patients with a BMI of 30-40 kg/m2 and no increase in bleeding events, this study will 
investigate dosing in an underrepresented population of patients with a BMI >40 kg/m2.5,11 Using 
the higher BMI cut-off will also allow for more patients with a weight above 150 kg which was 
also underrepresented in the trials.  
 
The purpose of this study is to determine an effective enoxaparin dosing strategy in medically ill, 
morbidly obese patients to achieve therapeutic anti-Xa levels. If an optimal regimen is discovered 
the ultimate goal will be designing a dosing and monitoring protocol.  
 
 


 
2. Design 
a. Sample 
i.  Inclusion  
1. Treatment dosing of enoxaparin (twice daily) 
2. BMI > 40 kg/m2  
ii. Exclusion 
1. <18 years of age 
2. Renal dysfunction (CrCl <30 ml/min) at any point during 
hospitalization while on enoxaparin  
3. Pregnancy 
4. Prisoners 
5. Active bleeding 
6. Already started on therapeutic enoxaparin and received >3 
consecutive doses   
7. Therapeutic enoxaparin use within the last 3 months for >5 
consecutive days 
b. Setting 
i. The location of study and data collection will take place in Grady hospital  
c. Recruitment 
i. Inpatients initiated on enoxaparin treatment doses will be prospectively 
identified using a Pharmacy Report to query medication orders in the 
electronic medical record system. 
ii. Consent will occur in patient’s hospital room once the medical team is 
notified of patient eligibility  
iii. Allowing 3 doses to be given prior to inclusion in the study will allow for 
equitable recruitment since clinical pharmacists may not be available 
during the evening hours to assist with initial dosing and recruitment 
d. Procedures 
i. Eligible patients will be approached while inpatient for written consent  
ii. Patients will be randomized in a 1:1 fashion into the 0.8mg/kg or 1 
mg/kg group (using total body weight) stratified by BMI 
1. Doses will be rounded to the nearest 10mg due to graduations 
on syringe 
iii. Initial anti-Xa levels  
1. Order levels 4 hours after at least three consecutive study doses 
of enoxaparin (will allow levels drawn between 3-5 hrs6,8,9). If 
the level is not drawn, it will be reordered after the next dose. 
2. Therapeutic anti-Xa: 0.5-1.1 IU/ml (GHS therapeutic range) 
3. Adjustments will be made according to the dosing nomogram 
until a therapeutic level is obtained (see appendix12). If a 
bleeding event occurs an anti-Xa level will be obtained.  
iv. Data Collection 
1. Baseline Data 
a. TBW, height, BMI  
b. BMI= TBW(kg)/height (m)2 
c. Age, Sex, Race 
d. Scr, CrCl (Cockcroft-Gault equation)  
e. Indication for treatment  
2. Post intervention 
a. Scr, CrCl 


b. Initial dose of enoxaparin (mg/kg and mg) 
c. Initial anti-Xa level and timing of level  
d. Number of hours post dose 
i. Level at 4 hours 
ii. Level within range of 3-5 hours  
e. Total number of doses received prior to level  
3. Subsequent doses of enoxaparin (mg/kg and mg) 
4. Subsequent anti-Xa levels after dosing adjustments 
5. Time to first therapeutic anti-Xa level 
6. Total days on enoxaparin 
7. Bleeding events 
a. Decrease in Hgb 
b. Site of bleed 
c. Blood product use 
d. INR at onset of bleeding event for patients on warfarin 
e. Additional anticoagulants and antiplatelets (date initiated 
and dose) 
f. 
Platelet count at onset of bleeding event 
g. Anti-Xa level at onset of bleeding event 
h. PT and/or aPTT if available 
v. Respondent Burden-Total respondent burden will be minimal and depend 
on the time it takes to consent. Laboratory work would have to be done 
for this medication regardless of whether they were in the study or not.  
e. Study Objectives/Outcomes 
i. Primary Objective 
1. To determine if enoxaparin dosing using 0.8mg/kg is more 
effective for achieving therapeutic steady state anti-Xa levels in 
morbidly obese patients when compared to 1 mg/kg dosing. 
(Morbid obesity is defined as a BMI > 40 kg/m2) 
ii. Secondary Objectives 
1. To compare time to therapeutic anti-Xa levels for both dosing 
regimens 
2. To compare anti-Xa levels for both dosing regimens 
3. To compare number of dose adjustments required to achieve 
therapeutic anti-Xa levels using a dosing nomogram 
4. To validate dosing nomogram used to adjust low molecular 
weight heparin doses 
5. To evaluate major and minor bleeding events  
iii. Primary Outcome 
1. Proportion of patients with an initial therapeutic anti-Xa level at 
steady state in each group 
a. Peak anti-Xa drawn 3-5 hours post dose after receiving 
at least 3 consecutive doses  
iv. Secondary Outcomes 
1. Time to therapeutic anti-Xa level for both groups 
2. Mean/Median therapeutic anti-Xa level for both groups 
3. Mean/Median number of dose adjustments required to achieve 
therapeutic anti-Xa level for both groups 
4. Proportion of patients with major and minor bleeding events (will 
follow until anti-Xa level is therapeutic)  


a. Major bleed: Hgb drop of >2g/dL, transfusion of 2 or 
more units of blood products, or retroperitoneal, 
intraocular, or intracranial hemorrhage13  
b. Minor bleed: bleeding events not meeting major bleed 
criteria 
f. Risks to participation 
i. Patients started on enoxaparin will be at risk for bleeding complications 
which is a known risk for this medication. Risk will be reduced by 
obtaining anti-Xa levels and adjusting the dose as needed. Other 
possible risks may be , anemia, decrease in platelets, elevation of liver 
enzymes, diarrhea, and nausea 
g. Benefits to subject or future benefits 
i. By completing this study a strategy for dosing enoxaparin may be 
established for obese patients that is safer and allows for quicker 
therapeutic levels.   
h. Data analysis 
i. Sample Size- In order to detect a 15% difference in the primary endpoint 
with a 2-sided significance level of 0.05, 50 patients per dosing group is 
needed to provide 80% power.  
ii. Statistical Analysis 
1. Descriptive statistics will be used for all variables. Primary 
outcome will be analyzed using chi-square. Time to event will be 
analyzed using survival curves and log rank test. Medians will be 
compared using wilcoxan rank test.  
 
3. Training 
CITI training will be completed by all personnel. Training on explaining risks and benefits 
during consent process and on using dosing nomogram will be done prior to initiation of 
study.  
 
4. Plans for data management and monitoring 
Safety data will be collected as mentioned above to monitor for adverse drug reactions, 
specifically bleeding. Patients with a decline in renal function that prompts a dose change 
will be excluded so that they may be put on a reduced dose listed in medication package 
insert.  
 
5. Confidentiality  
The data will be identifiable upon collection and will be kept on a password protected file 
on a computer in a locked office. The data will be de-identified after data analysis and 
only the study personnel will have access to the code that links identifiers to subjects. 
 
6. Informed Consent 
Informed written consent will be obtained in person while the patient is hospitalized.  
 
 
7. References 
 
1. Ogden CL.  Prevalence of obesity in the United States, 2009–2010. NCHS data brief, no 
82.  Hyattsville, MD: National Center for Health Statistics. 2012. 
2. Mensah GA. Obesity, metabolic syndrome, and type 2 diabetes: emerging epidemics and 
their cardiovascular implications. Cardiol Clin 2004;22:485-504. 


3. Spinler SA. Weight-based Dosing of Enoxaparin in Obese Patients with Non-ST-Segment 
Elevation Acute Coronary Syndromes: Results from the CRUSADE Initiative. 
Pharmacotherapy 2009;29:631-8. 
4. Lim W. Using Low Molecular Weight Heparin in Special Patient Populations. J Thromb 
Thrombolysis 2010; 29:233-40.  
5. Sanderink G. The Pharmacokinetics and Pharmacodynamics of Enoxaparin in Obese 
Volunteers. Clin Pharmacol Ther 2002;72:308-18. 
6. Hirsh J. Parenteral Anticoagulants: American College of Chest Physicians Evidence-Based 
Clinical Practice Guidelines. CHEST 2008. 133:141S-159S. 
7. Nutescu EA. Low Molecular Weight Heparins in Renal Impairment and Obesity: Available 
Evidence and Clinical Practice Recommendations Across Medical and Surgical Settings. 
Ann Pharmacother 2009;43:1064-83.  
8. Bazinet A. Dosage of Enoxaparin Among Obese and Renal Impairment Patients. Thromb 
Res 2005;1164:41-50. 
9. Deal EN. Evaluation of Therapeutic Anticoagulation with Enoxaparin and Associate Anti-
Xa Monitoring in Patients with Morbid Obesity: A Case Series. J Thromb Thrombolysis 
2011;32:188-194.  
10. Mahaffey KW. Obesity in Patients with Non-ST-Segment Elevation Acute Coronary 
Syndromes: Results from the SYNERGY trial. Int J Cardiol 2010; 139:123-33.  
11. Spinler SA. Safety and Efficacy of Unfractionated Heparin versus Enoxaparin in Patients 
who are Obese and Patients with Severe Renal Impairment: Analysis from the ESSENCE 
and TIMI 11B Studies. Am Heart J 2003;146:33-41.  
12. Monagle P. Antithrombotic Therapy in Children. CHEST 2001;119:344-370S.  
13. Enoxaparin [package insert].  Bridgewater, NJ: Sanofi-aventis; 2011.   
 
 


Appendix A. Dosing Nomogram for Adjusting Enoxaparin14  
 
 
 
Adapted from CHEST 2001 and adjusted per institutional procedures 
*Will obtain level if CrCl<30 ml/min or bleeding event
Anti-factor Xa 
level (IU/mL) 
Hold Next Dose 
Dose Change 
Repeat Anti-
Factor Xa* 
<0.35 
No 
Increase by 25% 
4h after next dose 
0.35-0.49 
No 
Increase by 10% 
4h after next dose 
0.5-1.1 
No 
No 
--- 
1.2-1.5 
No 
Decrease by 20% 
4h after next dose 
1.6-2.0 
No 
Decrease by 30% 
4h after next dose 
>2.0 
Until level is       
0.5 IU/mL 
Decrease by 40% 
4h after next dose