Once Daily Enoxaparin for Outpatient Treatment of Acute DVT and/or Pulmonary Embolism

Background and Significance:

Low molecular weight heparin (LMWH) as a "bridge" to warfarin has become the standard of care
for outpatient treatment of acute deep venous thrombosis (DVT). LMWH is also often prescribed
as a "bridge" to warfarin for patients with acute pulmonary embolism (PE). In the United
States, the FDA has approved enoxaparin only for twice daily dosing in outpatient treatment
of acute DVT. The FDA has also approved enoxaparin for treatment of DVT with or without PE,
but the FDA has not approved enoxaparin for the treatment of PE without DVT. The FDA has also
not approved once daily enoxaparin for any DVT or PE treatment indication for outpatients.

Once daily dosing of enoxaparin in outpatients with DVT alone, DVT with PE, or PE without DVT
will halve the number of required injections, facilitate outpatient treatment, and reduce
health care costs. For example, visiting nurses will make one visit daily instead of two
visits daily for those patients who are unable self-inject and for those patients who lack
family or friends to inject LMWH.

Merli et al randomized 900 hospitalized venous thromboembolism (VTE) patients with acute DVT
or PE to one of three treatment groups: 1) continuous infusion of unfractionated heparin
(UFH), 2) once daily enoxaparin 1.5mg/kg, or 3) twice daily enoxaparin 1mg/kg. All study
patients were inpatients. None were outpatients. They received once or twice daily enoxaparin
or UFH for at least five days and were "bridged" to warfarin. Patients were followed for
three months. Primary endpoints were recurrent DVT or PE. There were no significant
differences in recurrent DVT or PE among the 3 treatment groups. There were 12 recurrent VTE
events in the UFH group, 13 in the once daily enoxaparin group, and 9 in the twice daily
enoxaparin group.

The frequency of major hemorrhage did not differ among the three treatment groups. Major
hemorrhage occurred in 6 of 290 patients (2.1%) in the UFH group, 5 of 298 patients (1.7%) in
the once daily enoxaparin group, and 4 of 312 patients (1.3%) in the twice daily enoxaparin
group.

Merli et al showed that once daily enoxaparin was as effective and safe as twice daily
enoxaparin. But this study was done only among hospitalized patients with acute DVT or PE.
Treatment results in hospitalized patients do not necessarily apply to the outpatient
population. Therefore, the FDA has not approved outpatient DVT or PE treatment with once
daily enoxaparin.

The BWH Venous Thromboembolism Research Group has an outstanding track record for
investigator initiated trials. We have recently completed 2 investigator initiated trials
with enoxaparin for the treatment of PE. One trial was published in Thrombosis and
Haemostasis and the other is accepted for publication in Vascular Medicine.

Clinically stable PE patients with normal right ventricular size and function as assessed by
echocardiogram or chest CT scan are at very low risk of adverse clinical events. Either
imaging test is excellent for acquiring the information we need to document normal RV size
and function. These clinically stable PE patients with negative biomarkers (troponin) and
normal right ventricular function can be safely treated as outpatients.

Therefore, we wish to include in this trial clinically stable patients with acute PE who have
normal right ventricular size on chest CT in addition to patients with acute DVT. Chest CT
with a 4 chamber view with RVD/LVD measurement will be performed in all cases by a
radiologist with experience in this technique to confirm normal RV size on all PE patients.

In this investigator initiated trial, we will conduct a feasibility study with once daily
enoxaparin as a "bridge" to warfarin for outpatient treatment of acute DVT or PE.

Subject selection:

Physicians caring for DVT and PE patients in the noninvasive vascular lab, Emergency
Department, primary care office, and inpatient care units at Brigham and Women's Hospital
often summon our Group for consultation. Our Group will under these circumstances describe
this protocol. If the referring physician and the patient agrees, these patients will be
approached for enrollment by physician investigators from the research team.

We will study 40 patients with symptomatic DVT or PE confirmed by ultrasound or chest
computed tomography respectively and treat them with once daily enoxaparin as a bridge to
warfarin. In this case-control series, we will match 2 historical controls by age and gender
to every case. Controls who received twice daily enoxaparin as a "bridge" to warfarin for
acute venous thromboembolism will be matched from a retrospective study of previously
hospitalized patients. Additional characteristics of matched control group will include:
prior DVT or PE, cancer, heart disease, and pulmonary disease.

All patients enrolled in the study will receive enoxaparin 1.5mg/kg/day as a bridge to
warfarin, using at least 4 outpatient doses of enoxaparin and overlapping enoxaparin and
warfarin for at least 4 days.

Study Procedures:

Enrollment: Eligible patients with confirmed DVT and/or PE who are stable for outpatient
treatment will be approached for enrollment.

Following enrollment, patients will be started on enoxaparin 1.5mg/kg/day as a bridge to
warfarin. Patients will receive overlapping once daily enoxaparin and warfarin for at least 4
days.

After enrollment, patients will be started on warfarin 7.5 mg daily. Initial INR will be
checked on day 3 after starting warfarin. Thereafter, INR will be checked daily from day 4 to
day 7 and until INR is ≥ 2.0 for 2 consecutive days. Enoxaparin will be discontinued after a
minimum of 4 days and after 2 consecutive values ≥ 2.0. Once enoxaparin is discontinued
patients will continue oral warfarin alone. All INR tests can be done at any hospital,
including Brigham and Women's, or at a lab that is closer to patient's home.

Study investigators will perform anticoagulation management after discharge for 30 days; with
an initial office follow-up visit between days 7 and 13 and a final office visit between days
27 and 33. This will include clinical assessment, and blood testing of renal function and
international normalized ratio (INR). Each study visit will take up to 1 hour. Each blood
test will require 5 ml of patient's blood.

At the conclusion of the 30-day trial, responsibility for anticoagulation, including the
decision about its duration, will revert to the Primary Care Physician.

Biostatistical Analysis:

The sample size of 40 patients serves to assess the feasibility and safety of once daily
enoxaparin therapy as a bridge to warfarin for outpatient treatment of acute DVT and/or PE.

A composite endpoint of death, recurrent venous thromboembolism, and major hemorrhage will be
assessed at 30 days. Comparisons are made on an intention-to-treat basis. Separate analyses
will also be performed on each individual endpoint.

The statistical analysis plan will include specific exploratory subgroup analyses: DVT
without PE, PE without DVT, and combined DVT plus PE.

The statistical analysis will be by "intention to treat." In other words, once a patient is
recruited, that patient will be analyzed regardless of protocol violations and regardless of
missing data. No patient will be excluded from the analyses because of protocol violations,
missing data, or any other reason.

Chi-squared testing will be used for statistical analysis. For cells with 5 or fewer
patients, the Fisher's Exact Test will be used.

Efficacy and safety will be statistically evaluated in a composite endpoint. This composite
endpoint will include: Death, recurrent venous thromboembolism, and major hemorrhage at 30
days. Separate analyses will also be performed on each individual endpoint.

Inclusion Criteria:

1. Symptomatic acute deep venous thrombosis and/or pulmonary embolism confirmed by venous
ultrasound and/or CT scan.

2. Pulmonary embolism patients with normal right ventricular size on chest CT scan.

3. Age greater than 18 years

4. Anticipated discharge within 72 hours of admission

5. Written informed consent

Exclusion Criteria:

1. Pregnancy or intend to become pregnant

2. Patients requiring ongoing hospitalization > 72 hours

3. Hypersensitivity to heparin, pork products or enoxaparin

4. Creatinine > 2.0 mg/dl

5. Recurrent DVT and/or PE with oral anticoagulation

6. Surgery or medical procedure planned during the study that may pose a significant
bleeding risk

7. Prior history of heparin-induced thrombocytopenia

8. Inability to participate for follow up appointments and study visits

9. Life expectancy < 30 days

10. High risk of bleeding:

1. Active major bleeding within 30 days by GUSTO criteria

2. History of intracranial bleeding

3. Major surgery or trauma within 10 days

4. Head injury requiring hospitalization within 1 year

5. Intracranial tumor

6. Neurosurgery or non-cataract ophthalmologic surgery within 1 month

7. Thrombocytopenia