Apixaban for Routine Management of Upper Extremity Deep Venous Thrombosis

Background: Upper extremity deep vein thrombosis (UEDVT) constitutes approximately 10% of all
DVT. A recent increase in incidence is largely secondary to the increasing use of
peripherally inserted central venous catheters. Treatment for UEDVT is derived from evidence
for treatment of lower extremity deep vein thrombosis (LEDVT). No evidence exists for the use
of a direct oral anticoagulant (DOAC) for the treatment of UEDVT.

Population: Sequential patients identified within the Intermountain Healthcare system and
University of Utah Healthcare system with UEDVT defined as the formation of thrombus within
the internal jugular, subclavian, axillary, and brachial veins of the arm demonstrated by
imaging. Intervention: Apixaban 10 mg PO twice daily for 7 days followed by apixaban 5 mg
twice daily for 11 weeks.

Comparison: In the primary analysis, the principal investigator will report the rate of
clinically overt objective VTE and VTE-related death in comparison to the rate reported upon
literature review ("reference value in the literature"). If the confidence interval for this
rate excludes the commonly accepted threshold event rate of 4%, the principal investigator
will conclude that treatment with apixaban is noninferior, and therefore a clinically valid
approach to treat UEDVT. As a secondary analysis the principal investigator will compare the
rate of the primary efficacy outcome and primary safety outcome with a historical control of
case matched patients with UEDVT ("historical control") treated with therapy conventional
(low molecular weight heparin plus warfarin) prior to the approval of DOACs.

Sample Size: A sample size of 357 patients who meet eligibility criteria was chosen so that
an exact 95% confidence interval would exclude an event rate of venous thromboembolism (VTE)
in the observation cohort of 4%. The principal investigator will add 5% for anticipated
withdrawal to assure adequate patient enrollment in the case of patient withdrawal and enroll
375 patients.

Outcome: 90 day rate of new or recurrent objectively confirmed symptomatic venous thrombosis
and VTE-related death. The primary safety outcome is major bleeding and clinically relevant
nonmajor bleeding.

Inclusion Criteria:

- Be ≥ 18 years of age

- Have received no more than four (4) doses of any anticoagulant, or intravenous and
bridging heparin for longer than 60 hours

- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
the start of study drug.

- Women must not be breastfeeding

- WOCBP must agree to follow instructions for method(s) of contraception for the
duration of treatment with study drug apixaban plus 5 half-lives of study drug
apixaban (3 days) plus 30 days (duration of ovulatory cycle) for a total of 33 days
post-treatment completion.

- Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with study drug apixaban plus
5 half-lives of the study drug apixaban (3 days) plus 90 days (duration of sperm
turnover) for a total of 93 days post-treatment completion.

- Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However WOCBP must still undergo pregnancy testing as
described in this section.

Exclusion Criteria:

- Another indication for long-term anticoagulation for which no FDA approval of apixaban
exists (e.g. prosthetic heart valves)

- Life expectancy of less than 6 months

- Unable to engage in reliable follow-up as per protocol

- Participating in a conflicting clinical trial or has participated in a trial within
the last 30 days

- Receiving concomitant dual antiplatelet therapy

- Requires aspirin dose of greater than 165 mg daily

- A hemoglobin level of less than 8 mg per deciliter

- A platelet count of less than 50,000 per cubic millimeter

- A calculated creatinine clearance of less than 25 mL per minute

- Alanine aminotransferase or aspartate aminotransferase level greater than 2 times the
upper limit of the normal range

- A total bilirubin more than 1.5 times the upper limit of the normal range.

- Active cancer for which treatment (chemotherapy/radiation therapy) is being delivered,
is imminent, or has been delivered within the last 6 months

- For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should
be decreased by 50% when coadministered with drugs that are strong dual inhibitors of
CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin). For
patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministation with
strong dual inhibitors of CYP3A4 and P-gp.

- Intend pregnancy or breastfeeding within the next year

- Known allergy to apixaban, rivaroxaban, or edoxaban

- Active pathological bleeding.

- Any condition that at the discretion of the investigator is thought to prohibit active
participation and follow-up in the trial

- UEDVT that occurs while therapeutic anticoagulation is being taken by the patient
("event on therapy")

- The patient has concomitant VTE diagnosed elsewhere (e.g. DVT Of the lower extremity
or PE)