Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT

Background and Introduction:

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in
hospitalized patients. It is a well-known complication in patients after major surgery or
trauma. More recently, medically ill patients have been identified as another high risk group
with up to 15% of patients experiencing VTE in the absence of prophylaxis. 1 Several studies
have found the use of enoxaparin, dalteparin, and fondaparinux to be safe and effective in
reducing risk of VTE by 45% to 63% in medically ill patients. 1-3 Additionally, enoxaparin
has been found to be at least as safe and effective as unfractionated heparin for VTE
prophylaxis. 4 Enoxaparin 40 mg once daily has been shown to be a safe and effective
prophylactic therapy in hospitalized patients. 1

In thromboprophylaxis studies, including those investigating enoxaparin 40 mg once daily,
morbidly obese patients (greater than or equal to 35 kg/m2) have been grossly under-enrolled.
This is problematic for several reasons. First, the drug distribution is weight dependent and
therefore, anticoagulant levels will differ according to a patient's weight. 5 Secondly, the
FDA approved doses are fixed doses that do not take into account body weight. Thirdly, obese
patients are at greater risk for failure in preventing VTE and obese patients are probably at
greater risk for developing VTE. 6 Lastly, morbidly obese patients are becoming quite common
as the population as a whole is becoming more obese.

Even with this information, there are no standards of VTE prophylaxis in obese patients.
Optimal means of delivering safe and effective thromboprophylaxis in this group is unknown.
When using LMWH's, consensus recommendations have been to monitor peak anti-Xa activity
targeting a level of 0.1-0.2 units/mL. 5 However, many hospitals do not have access to
anti-Xa monitoring. Studies evaluating the predictability of weight-based prophylactic dosing
of tinzaparin have demonstrated that anti-Xa levels are predictably achieved and therefore,
laboratory monitoring may not be necessary with this dosing strategy.7 However, tinzaparin is
not widely utilized in the U.S. and uncertainties remain about whether predictable anti-Xa
levels can be achieved with a weight-based prophylactic regimen using the more commonly used
drug enoxaparin. If weight-based dosing with enoxaparin is shown to result in predictable
anti-Xa activity in obese patients, the need for monitoring would be obviated.

Objectives: The primary objective is to evaluate the predictability in achieving target
anti-Xa activity levels in morbidly obese medically ill patients using weight-adjusted (0.5
mg/kg) once daily prophylactic dose of enoxaparin. The secondary objective is to gain
information to evaluate the pharmacokinetic curve of enoxaparin in obese patients over 18
hours after the second dose.

Participant Selection Criteria: VTE risk will be evaluated with an institutionally utilized
risk stratification scheme. This risk stratification scheme which was drafted by a
multi-disciplinary panel, represents standard of care for medically ill patients at the
University of Utah.

Inclusion Criteria: Medically ill patients who are greater than 18 years of age who have a
body mass index (BMI) greater than or equal to 35 kg/m2 who are admitted to the University of
Utah Medical Center, are at risk for VTE, and are eligible for pharmacological prophylaxis as
determined by patient's provider will be consented for the study.

Exclusion Criteria: Patients who are pregnant (a urine HCG will be performed if a female of
child-bearing age is not on reliable birth control, or if otherwise clinically indicated),
are currently on therapeutic anticoagulation, have a bleeding disorder, platelet count of
less than 100,000/mL, coagulopathy, active bleeding, creatinine clearance less than 30 mL/min
(based on Cockcroft-Gault equation, and rounding serum creatinine to 1 in patients greater
than 65 years), or recent (within 14 days) stroke, surgery or trauma will be excluded.

Design: This is a single arm study enrolling consecutive eligible patients admitted to the
University of Utah Medical Center. This is a descriptive study evaluating the feasibility and
predictability of administering weight-adjusted enoxaparin (0.5mg/kg once daily) to achieve
recommended target peak anti-Xa levels in patients at extreme body weight. The hypothesis is
that weight-adjusted prophylaxis will reliably achieve recommended target anti-Xa levels. If
so, this would obviate the future need for routine anti-Xa monitoring using this
pharmacologic regimen.

Additionally, there will also be a parallel cohort evaluating a day 2 pharmacokinetic curve
by 5-serial anti-Xa activity measurements in a subset of up to 2-3 patients in each weight
group.

Study procedures: Consecutive eligible patients will be enrolled if informed consent is
given. Consent will be obtained in the University Hospital, mainly on the Internal Medicine
Floor. It will be obtained by the one of the study co-investigators. At least one person who
is obtaining consent will be available to consent patients any time of day and will have
adequate time to exchange information and answer questions between investigator and
participant.

The study protocol uses a VTE prevention regimen that employs rational pharmacologic
principles and is in line with published recommendations for prophylaxis in this patient
population. In consideration of having a comparator cohort group, we would consider it to be
unethical to have a cohort group receiving enoxaparin 40 mg subcutaneously once daily as a
comparator group because pharmacologic data strongly suggests that effective levels of
anticoagulation would not be achieved in this population of patients. 8 Informed consent was
felt optimal in order to allow patients to fully understand that this regimen, although it is
an acceptable standard of care, is being employed under the broader context of a study
whereby other patient data will be collected and recorded in prospective fashion. Once
informed consent is obtained, patients will begin VTE prophylaxis with enoxaparin 0.5 mg/kg
subcutaneously once a day. Peak anti-Xa activity will be obtained in all patients through a
venipuncture 4-6 hours after the first or second dose has been given. Five milliliters of
blood will be drawn. This is the amount of blood that is needed for this laboratory test to
be performed. Baseline clinical and demographic information will be obtained and recorded on
standard case reporting forms, CRF (see Appendix B). Patients will continue prophylaxis as
deemed necessary by their attending physician through the duration of their hospital stay or
unless dictated otherwise by the patient's attending physician. Adverse events such as VTE,
bleeding event, or thrombocytopenia will be recorded during the hospital stay (see Appendix
C).

If patients consent to do the additional testing, this will be marked on the consent form.
These patients will have anti-Xa levels drawn before the first enoxaparin dose, and then at
4h, 6h, 12h, and 18h after the second dose of enoxaparin. If the 12h anti-Xa level is
obtained and is less than 0.05 units/mL, then the 18 hour blood test can be eliminated. The
purpose of this section is to provide us with information to evaluate the pharmacokinetic
curve of enoxaparin in obese patients over 18 hours.

Inclusion Criteria:

- Obese patients (BMI>35kg/m2)>18 years of age admitted to medical service and
considered at increased risk for DVT and whom pharmacological prophylaxis is being
considered by treating physician.

Exclusion Criteria:

- Pregnancy

- Currently on alternate therapeutic anticoagulant (warfarin, heparin, LMWH)

- Platelet count <100,000, CrCl <30ml/min, or coagulopathy

- recent (within 14 d) stroke, trauma, or major surgical procedure

- Active bleeding or deemed at increased bleeding risk by the investigator.