The design and rationale for the Acute Medically Ill

Venous Thromboembolism Prevention with Extended

Duration Betrixaban (APEX) study
Alexander T. Cohen, MD, a Robert Harrington, MD, b Samuel Z. Goldhaber, MD, c Russell Hull, MD, d
C. Michael Gibson, MD, c Adrian F. Hernandez, MD, MHS, e Michael M. Kitt, MD, f,g and Todd J. Lorenz, MD h
London, United Kingdom

Randomized clinical trials have identified a population of acute medically ill patients who remain at risk for venous
thromboembolism (VTE) beyond the standard duration of therapy and hospital discharge. The aim of the APEX study is to
determine whether extended administration of oral betrixaban (3542 days) is superior to a standard short course of
prophylaxis with subcutaneous enoxaparin (10 4 days followed by placebo) in patients with known risk factors for postdischarge VTE. Patients initially are randomized to receive either betrixaban or enoxaparin (and matching placebo) in a
double dummy design. Following a standard duration period of enoxaparin treatment (with placebo tablets) or betrixaban
(with placebo injections), patients receive only betrixaban (or alternative matching placebo).
Patients are considered for enrollment if they are older than 40 years, have a specified medical illness, and restricted mobility.
They must also meet the APEX criteria for increased VTE risk (aged 75 years, baseline D-Dimer 2 upper the limit of normal,
or 2 additional ancillary risk factors for VTE). The primary efficacy end point is the composite of asymptomatic proximal deep
venous thrombosis, symptomatic deep venous thrombosis, non-fatal (pulmonary embolus) pulmonary embolism, or VTE-related
death through day 35. The primary safety outcome is the occurrence of major bleeding. We hypothesize that extended duration
betrixaban VTE prophylaxis will be safe and more effective than standard short duration enoxaparin in preventing VTE in acute
medically ill patients with known risk factors for post hospital discharge VTE. (Am Heart J 2014;167:335-41.)

Venous thromboembolism (VTE) is clinically manifest

as deep venous thromboembolism (DVT) and/or pulmonary embolism (PE) and has been identified by the
Surgeon General as being one of the most preventable
causes of in-hospital morbidity and mortality (http://
www.surgeongeneral.gov/library/calls/deepvein/call-toaction-on-dvt-2008.pdf). Hospitalized medically ill patients are at significant risk of experiencing VTE events

From the aDepartment of Haematological Medicine, King's College Hospital, London,

United Kingdom, bDepartment of Medicine, Stanford University, School of Medicine,
Stanford, CA, cHarvard Medical School, Boston, MA, dUniversity of Calgary, Alberta,
Canada, eDuke Clinical Research Institute, Durham, NC, fAfferent Pharmaceuticals, Inc,
San Mateo, CA, gFormerly of Portola Pharmaceuticals, Inc., South San Francisco, CA, and
h
Portola Pharmaceuticals, Inc, South San Francisco, CA.
Debabrata Mukherjee, MD, served as guest editor for this article.
NCT01583218.
Submitted August 6, 2013; accepted November 15, 2013.
Reprint requests: Alexander T. Cohen MD, Department of Haematological Medicine,
Denmark Hill, London SE5 9RS, UK.
E-mail: Alexander.cohen@kcl.ac.uk
0002-8703 2014, The Authors. Published by Mosby, Inc.
Open access under CC BY-NC-SA license.

http://dx.doi.org/10.1016/j.ahj.2013.11.006

both during their hospital stay and after discharge 1

Current medical practice using prophylaxis for VTE is
based on randomized trials of short-term, low-dose
pharmacologic thromboprophylaxis that have demonstrated a relative risk reduction of 45-64% of VTE in acute
medically ill patients (MEDENOX 2; PREVENT 3; ARTEMIS 4).
However, patients remain at risk for VTE for up to 3
months following hospital discharge, with the peak
incidence occurring within the first 4 weeks. 5,6
Extended duration thromboprophylaxis regimens have
successfully reduced the incidence of VTE in postoperative patients, however acute, medically ill patients
have not have not been shown to obtain a favorable
benefit to risk ratio from longer periods of prophylaxis.
Specifically, three trials have been conducted to examine
the clinical utility of extended prophylaxis in such
patientsEXCLAIM, 7 MAGELLAN, 8 and ADOPT. 9 The
EXCLAIM study, which examined the effect of primarily
post-hospital enoxaparin on the occurrence of VTE,
showed a 44% reduction in VTE and demonstrated
there was an apparent favorable treatment benefit in
patients with the highest level (Type 1) of immobility. An
approximate 2.5 fold increase in major bleeding 8 was
seen but there was a statistically significant modest
decrease in symptomatic DVT. The MAGELLAN study

American Heart Journal

March 2014

336 Cohen et al

Figure

APEX study design.

evaluated the oral factor Xa inhibitor, rivaroxaban, for

both in-hospital and extended VTE prophylaxis demonstrated a significant reduction in the VTE rate at 35 days
with rivaroxaban, however this benefit was offset by a
significant increase in major bleeding. 9 The ADOPT study
evaluated apixaban for extended VTE prophylaxis in acute
medically ill patients, had event rates that were lower than
expected (likely due to lower mean age, greater mobility
and fewer additional risk factors for VTE). A significant
reduction in VTE events was not observed in apixaban
treated patients. 10 There was a higher than expected rate
of dropouts (30%) that did not have the 30-day ultrasound
performed and were inevaluable for the primary efficacy
endpoint. Like the other two studies an approximate
2.5-fold increase in major bleeding was also seen.
The MAGELLAN enrolled patients demonstrated a
statistically significant reduction in the primary efficacy
endpoint, but excess bleeding compromised net clinical
benefit. This may have been due to its use of once daily
dosing, which resulted in relatively high drug levels during
the first few hours after administration. The ADOPT study
enrolled patients at lower risk than MAGELLAN (eg, over
two thirds of patients were only moderately, not severely
immobilized) and therefore had a very low incidence of
efficacy events (3.06% in the comparator arm). The safety
profile of apixaban in this indication, however, was quite
acceptable, with only 1% of patients in the apixaban arm
experiencing a major bleeding event.
In designing the APEX study, the Executive Committee
has specified a patient population that is at higher risk of

VTE than was included in either MAGELLAN or ADOPT.

In addition, the once-daily dosing regimen of betrixaban
selected for APEX will provide a similar level of
anticoagulation as the twice daily regimen of apixaban
used in ADOPT. The APEX study has employed the
lessons learned from these previous trials of extended
prophylaxis to identify the patients at highest risk of VTE
in the medically ill population to test the hypothesis that
extended prophylaxis with betrixaban will have a
positive risk/benefit profile over the standard of care,
which is often limited to in-hospital prophylaxis with
enoxaparin. The APEX trial will therefore test two
hypotheses: that betrixaban is a safe and efficacious
drug for VTE prophylaxis, and that an extended duration
of prophylaxis in such patients improves the outcomes
over the current standard of care (Figure).
Betrixaban is a potent and specific inhibitor of human
factor Xa (fXa) activity that acts by competitively binding
to the active site of fXa, preventing its ability to convert
prothrombin to thrombin. Betrixaban is rapidly absorbed
with mean peak concentrations occurring within 3 to 4
hours after oral administration. Excretion is mostly
unchanged through the bile with renal excretion
accounting for approximately 57% of the orally administered dose. While betrixaban is not a substrate for major
cytochrome P450 enzymes, it is a substrate for
permeability glycoprotein (P-gp). Potent inhibitors of
P-gp (ie, ketoconazole, amiodarone, diltiazem) increase
betrixaban concentrations around twofold. To date,
betrixaban has been studied in 22 Phase I and II studies

American Heart Journal

Volume 167, Number 3

performed in more than 1,400 subjects. The EXPLORE

Xa 11 study for stroke prevention in atrial fibrillation and
EXPERT 12 study in orthopaedic surgery were used with
pharmacometric modeling to determine the safety
profile and most pharmacodynamically appropriate
doses of betrixaban in the medical patient setting.
Mainly elderly patients were enrolled in the atrial
fibrillation study.
The APEX study is designed to assess the safety and
efficacy of extended duration oral betrixaban compared
with standard duration enoxaparin for thromboprophylaxis
in acutely ill medical patients. Based on the results of Phase
II studies and pharmacometric dose modeling, an 80 mg
dose of betrixaban will be used in all patients except those
with severe renal insufficiency (ie, with a creatinine
clearance b30 mL/min) and those taking a concomitant
strong P-gp inhibitor. In these groups, a reduced dose of
betrixaban 40 mg, that demonstrates a profile of thrombin
generation inhibition similar to the 80 mg dose in the main
strata, will be used.
Since betrixaban has such a low fractional renal
excretion, the APEX study will allow enrollment of
patients with severe renal insufficiency, ie, those with a
creatinine clearance b30 mL/min, who do not require
dialysis. These patients have both a high risk of bleeding
and a high risk of VTE, and have traditionally been
excluded from clinical trials. APEX will represent the first
trial of extended prophylaxis of VTE in the acute
medically ill to include such patients.
The dose of enoxaparin will also be decreased in
patients with severe renal dysfunction to be consistent
with prescribing guidance. In fact, although there is little
data on the efficacy of lower doses, the recommended
dose of enoxaparin in such patients varies worldwide
between 20 and 30 mg, depending on the specific
regulatory authority. In order to harmonize this subgroup
across the worldwide scope of APEX, a dose of 20 mg of
enoxaparin (or matching placebo) will be used in all
patients with severe renal dysfunction that are enrolled
in APEX.

Study objectives
The primary objective of the APEX study is to
demonstrate the superiority of extended duration (35
42 days) anticoagulation with betrixaban as compared to
the standard of care anticoagulation with enoxaparin (6
14 days) for prevention of VTE in patients who are at risk
due to acute medical illness.

Methods
Study design
APEX is a prospective, randomized, double-blind, doubledummy, parallel group, multicenter, multi-national clinical trial.
The study is being conducted in accordance with the
Declaration of Helsinki and all applicable local regulations.

Cohen et al 337

Table I. Participating sites and countries

Geographic region and
countries
Africa
South Africa
Asia
Australia
India
Singapore
Europe
Austria
Belgium
Bulgaria
Croatia
Czech Republic
Denmark
Estonia
France
Germany
Hungary
Israel
Italy
Latvia
Lithuania
Poland
Romania
Russia
Spain
United Kingdom
Ukraine
North America
Canada
United States
South America
Argentina
Brazil
Chile
Peru

Number of investigational
sites

4
6
0
2
8
5
13
7
13
8
3
22
17
15
10
9
5
9
15
8
13
15
5
15
3
51
9
9
4
7

Current as of Oct 22, 2013.

The APEX trial is registered at clinicaltrials.gov (NCT01583218).

Approval of the protocol has been obtained from the
appropriate ethics committee or institutional review board for
all participating centers.

Study sites
This study will be conducted at approximately 400 sites in
North America, Europe, South America, South Africa, Asia, and
Australia. Table I details the countries and respective sites
enrolled per country as of October 28, 2013.

Patient population
Subjects are considered for enrollment in APEX if they are
hospitalized for a specified acute medical illness, have
additional risk factors for VTE, have been and are expected
to be severely immobilized for 24 hours during the current
hospitalization, and are expected to be moderately and/or
severely immobilized for at least 4 days after admission
randomization with anticipated survival of at least 8 weeks.
The full inclusion and exclusion criteria are listed in Table II.
Pre-specified acute medical illness prompting hospitalization

American Heart Journal

March 2014

338 Cohen et al

Table II. Inclusion and exclusion criteria for APEX

Inclusion criteria

Exclusion criteria

Patients aged 40 y
1. Hospitalized N96 h before randomization
A. Aged 4060 must have additional risk factor of previous VTE or history of cancer and 2. Unable to take enteral feeding
an additional risk factor listed below
B. Aged 6074 with either D-Dimer level 2 ULN within 4 days before randomization or 3. At increased risk of bleeding:
at least two additional VTE risk factors:
Previous VTE or superficial vein thrombosis
a. History of clinical significant bleeding within previous 6
months
Obesity (BMI N35)
b. History of any significant GI, pulmonary, or urogenital
bleeding, chronic peptic ulcer disease or gastritis
Chronic venous insufficiency
4. Concomitant diagnosis likely to require major surgery or
invasive procedure within 3 months
Lower extremity paresis, hemiparesis, or hemiparalysis
5. Major or ophthalmic surgery, biopsy of parenchymal organ,
or serious trauma in previous 3 months
Hormone therapy
6. Known history of bronchiectasis or active lung cancer
History of cancer excluding non-melanoma skin carcinoma
7. End-stage renal disease with CrCl b15 mL/min or requiring
dialysis
Chronic heart failure (NYHA III or IV)
8. Previous history of or concurrent intracranial bleeding
Chronic respiratory failure
9. History of severe head trauma or trauma within previous 3
months
Active collagen vascular disease associated with limited mobility
10. Known intracranial lesions
Acute infectious disease contributing to current hospitalization
11. Concomitant conditions, such as:
Current use of erythropoiesis stimulating agents
12. Severe renal insufficiency and requiring use of a strong P-gp
inhibitor
Inherited or acquired thrombophilia
13. Contraindications to anticoagulant therapy
C. Age 75 years with or without additional risk factors All patients must have an 14. Known liver function test abnormalities (AST/ALT N3 ULN
anticipated severe immobilization at least 24 hours before or after randomization and or ALP N2 ULN), active liver disease, or cirrhosis
anticipated severe or moderate immobility totaling 4 days
Severe immobility: totally confined by illness to bed or chair for 100% of time
15. Uncontrolled HIV infection
Moderate immobility: confined by illness to bed for more than 50% of time during 16. Concurrent or history of alcohol or drug abuse within 1 year
daytime hours but may spend up to 50% of time in bedside chair. Unable to ambulate 10 of enrollment
meters without assistance
D. Expected hospitalization 3 days
17. Shock requiring vasopressors or not responding to simple
volume replacement
18. History of hypersensitivity to study drugs
19. Pregnancy or breastfeeding

includes acutely decompensated heart failure with baseline

New York Heart Association class II or greater, presenting as
and class III or IV on admission, acute respiratory failure in
patients with chronic lung disease, acute infection without
septic shock, acute rheumatic disorders, and acute ischemic
stroke with lower extremity hemiparesis or hemiparalysis.
Subjects must also have at least 1 of the following baseline
factors that have been associated with increased risk of VTE in
previous studies: age 75 years (as seen in EXLCAIM 13); have a
baseline level of D-dimer level 2 upper limit of normal
(ULN) before randomization (as noted in subgroup analyses
from MAGELLAN 14); or at least 2 additional clinical risk factors
for VTE (as observed in 1). The full list of ancillary risk factors as
well as inclusion/exclusion criteria are detailed in Table II. All
patients (or their legally appointed health care representative)
are required to provide informed consent.

Randomization and study drug administration

Patients who meet criteria for enrollment are randomized 1:1
to one of two treatment groups using an interactive voice
response system. Randomization kits include either betrixaban
and enoxaparin placebo or enoxaparin and betrixaban placebo.
Patients continue to receive betrixaban or betrixaban placebo

for 35 to 42 days after randomization and enoxaparin or

enoxaparin placebo a total of 6 to 14 days. Patients who leave
the hospital early are instructed to continue its enoxaparin
administration as an outpatient before a minimum of 6 total days
as per the package insert.
Subjects receive betrixaban (or matching placebo) by mouth
once daily during the active treatment period. On Day 1,
subjects receive two 80 mg capsules of betrixaban to achieve
steady state plasma concentrations rapidly. A single daily dose of
80 mg once is taken thereafter for a total of 35 to 42 days.
Patients receiving a concomitant strong P-gp inhibitor or who
have severe renal insufficiency (CrCl 15 mL/min and b30 mL/
min) receive a reduced dose of 80 mg initially and 40 mg once
daily thereafter. Enoxaparin (or matching placebo) is also
administered at a dose of 40 mg subcutaneously daily (20 mg
for those with severe renal insufficiencyCrCl 15 mL/min
and b30 mL/min).

Study procedures
Potential subjects are screened for eligibility and demographics and a medical history are recorded. A physical
examination, an electrocardiogram, and blood sampling for
clinical chemistry (electrolytes, liver function tests, and C-

American Heart Journal

Volume 167, Number 3

reactive protein), hematology (complete blood count), and

coagulation (prothrombin time, activated thromboplastin time,
D-dimer) are performed. Serum pregnancy test is performed for
women of childbearing potential and NT-proBNP for patients
admitted for heart failure. Additionally, an objective mobility
assessment of the patients ability to ambulate and time spent
out of bed is performed.
The second visit (Visit 2) occurs on the day of hospital
discharge or no later than day 14 after randomization,
pharmacokinetic assessment is made. The third visit (Visit 3)
occurs between day 35 and 42 and the bilateral lower
extremity venous ultrasound is performed. The final contact
occurs at Visit 4 between 3035 days after Visit 3 and may be
done by telephone if necessary, to determine whether a posttreatment VTE may have occurred and to check for any late
adverse events. All data on subjects is collected using
electronic data capture and is recorded in the eCRF and
verified by the investigator.

Ultrasonography procedures
The only mandatory ultrasound for subjects enrolled in APEX
occurs at Visit 3. Suspected DVT prior to Visit 3 is evaluated by
lower extremity venous ultrasonography or venography.
Suspected cases of PE are investigated by spiral CT, ventilation-perfusion lung scan, or pulmonary angiography. Unless VTE
is confirmed, subjects continue to receive study medication. For
patients who discontinue study medication prior to day 35,
bilateral lower extremity venous ultrasound is still to be
performed at Visit 3. These ultrasounds are performed locally
and are obtained blinded, anonymized and electronically sent to
the core lab for interpretation.
The lower extremity venous ultrasound evaluates for asymptomatic proximal DVT by visualizing the common femoral vein,
deep femoral vein, femoral vein, popliteal vein, and trifurcation
of the calf veins. The lack of compressibility of a vein under
probe pressure is the primary criterion for presence of DVT. The
Central Ultrasound Core Lab, which is blinded to treatment
assignment, adjudicates all scheduled ultrasounds.

Efficacy and safety outcomes

The primary efficacy outcome for the trial is the
composite occurrence of any of the following events
from randomisation through to Visit 3: asymptomatic
proximal DVT (as detected by ultrasound), symptomatic
DVT (proximal or distal), non-fatal PE, or VTE-related
death. The secondary efficacy outcomes (in the order of
statistical testing) include the composite of symptomatic
VTE, non-fatal PE, or VTE-related mortality through Visit
3, as well as the composite of asymptomatic proximal
VTE (as detected by ultrasound), symptomatic DVT
(proximal or distal), non-fatal PE or all-cause mortality.
Deaths are classified as VTE-related, due to bleeding, or
due to other causes and are adjudicated by the blinded
Clinical Events Committee.
The primary safety outcome is the occurrence of major
bleeding (as defined in Schulman et al. 8) through 7 days
after discontinuation of all study medications. Bleeding
events are classified as major bleeding, clinically relevant

Cohen et al 339

non-major bleeding (CRNM), and minimal bleeding.

Clinically overt bleeding is defined as major bleeding
when it is directly observed and is associated with a
reduction in hemoglobin of at least 2 g/dL, or requires a
transfusion of 2 U of blood, or symptomatic bleeding
occurs in a critical area or organ, or results in a fatal
outcome. CRNM is defined as overt bleeding not meeting
criteria for major bleeding but associated with medical
intervention, unscheduled contact with a physician,
cessation of study treatment, or associated with discomfort for the patient. Additional parameters pertaining to
economic and quality of life indicators are also assessed,
including length of hospital stay, intensive care unit days
during initial hospitalization, re-hospitalization rates,
interventions to treat bleeding episodes, and interventions to treat VTE.
The APEX study has convened an Independent
Monitoring Committee that will be composed of independent experts in the fields of internal medicine and
biostatistics. It will meet frequently (at 250, 750, 1500,
3000 and 4500 patients with data) during the trial to
insure safety of the study population.

Statistical analyses and sample size

The safety population consists of all patients randomized and treated with at least one dose of study
medication. All safety analyses will be performed by actual
treatment received. The efficacy analysis population for
the primary and secondary endpoints will be a modified
intent-to-treat population consisting of all patients who
have taken at least one dose of study medication and have
had an adequate assessment of events. An adequate
assessment of events for the primary efficacy end point
is defined as an interpretable venous ultrasound at Visit 3,
the occurrence of symptomatic events as adjudicated by
the Clinical Events Committee or a VTE-related death.

Efficacy analysis
All efficacy statistical tests will be one sided and
performed at the =.025 significance level (ie, .05 2sided). If the superiority of the primary composite
outcome is established, then the secondary outcomes
will be tested sequentially. Analysis of all efficacy
outcomes will be conducted via Mantel-Haenszel tests
stratified by the two randomization stratification factors:
elevated D-dimer at baseline (2 the upper limit of
normal) and dosing assignment criteria (ie, either 80 mg
or 40 mg in those with severe renal dysfunction or
receiving a concomitant strong P-gp inhibitor). All results
will be presented in terms of relative risk reductions. The
actual level of significance used in the final analysis of the
primary and secondary efficacy variables will be 0.025
(0.00005 number of safety looks).
There will be a single interim analysis for futility of the
primary outcome when approximately 60% of the

American Heart Journal

March 2014

340 Cohen et al

primary outcome evaluable patients have data. An

O'Brien-Fleming boundary will be used resulting in a 1sided =.0011 spent for futility if 50% of evaluable
patients are examined.

Safety analysis
All primary and secondary safety outcomes will be
tested using 2-sided unadjusted 2 tests with Type I error
rate of 5%. The incidence of major CRNM bleeding will
comprise the primary and secondary safety outcome
analyses, respectively.
Determination of sample size
The sample size was calculated to provide 90% power
for the primary outcomes at the one-sided =.005 level
(ie, 0.01 2-sided). Based on results of the relevant
subgroups from MAGELLAN, we estimated an event
rate of the primary endpoint of 7.5% for the control group
at day 35. With a control group event rate of 7.5%, an
assumed relative risk reduction of 35% at day 35
(conservatively based on the Exclaim study), and a single
interim analysis for futility after ~50% of the evaluable
patients have completed the trial, a sample size of 2,568
patients per treatment group with evaluable primary
outcome data will provide 90% power for concluding
superiority at the one-sided =.005 level. Based on the
three previous studies, we assume that 25% of subjects
will not be evaluable for the primary efficacy outcome,
therefore 3,425 patients per treatment group (6,850 in
total) will be required.

Discussion
EXCLAIM, 7 MAGELLAN, 9 and ADOPT 1 were unsuccessful in enrolling a population both at high enough risk
of VTE and low enough risk of bleeding to warrant
extended prophylaxis. The APEX trial aims to identify the
sweet spot (the right population, prophylaxis duration
and pharmacologic regimen) to provide effective and safe
extended duration prophylaxis.
The APEX trial has several unique characteristics that
are important in the evaluation of extended duration
VTE prophylaxis.
First, the mobility criteria in APEX are more stringent
than in the EXCLAIM and ADOPT studies, thus focusing
on truly at-risk patients. APEX will focus on patients
expected to be severely immobilized for 24 hours and
either moderately or severely immobilized for at least 4
days during their hospitalization. Second, subjects in
APEX must have additional criteria that place them at
high risk of VTE which include either: a pre-randomization D-dimer level of 2 ULN; age N75 of years; or 2
additional VTE risk factors other than the admitting
medical diagnosis. In a subgroup analysis of MAGELLAN,
patients in the control group with a D-dimer N2 ULN
were at significantly increased risk of VTE at day 35 (9.3%

vs. 2.2%). 14 Additionally, prior studies have identified

older age as independently associated with risk of VTE in
hospitalized medical patients (MEDENOX, 2 MAGELLAN 9
and PREVENT 3). This focus on medical patients at highrisk of VTE events will identify a group likely to benefit
from extended duration anticoagulation and is in
agreement with changes in recent guideline recommendations to focus thromboprophylaxis efforts on high-risk
patients. 15
Third, the exclusion criteria are designed to select a
population of patients at a reduced risk of bleeding
compared with the previous studies. Fourth, the dose
adjustments and the lack of CYP 3A/4 interactions
allow a wider range of patients with both co-morbidity
such as severe renal impairment and co-medications
such as p-Gp and CYP 3A4 modifiers to be included in
the study. This will lead to results that are more
generalizable.
Finally, unlike prior studies in extended duration
prophylaxis, there will not be an interim 10-day
ultrasound as part of APEX. Part of the criticism of
routine 10-day ultrasonography in these prior trials is that
it is inconsistent with standard of care clinical practice. In
addition, the identification of asymptomatic DVT at 10
days may both alter the natural history of VTE and as well
as result in the treatment of potentially clinically
insignificant thrombosis. In a trial aimed at testing the
hypothesis that extended anticoagulation is superior to
standard duration enoxaparin, an interim assessment of
asymptomatic events is not warranted. Omission of a
mandatory Day 10 ultrasound will result in the study of
more symptomatic events.
There are currently no approved therapies for extended duration VTE prophylaxis in immobilized medically ill
patients. APEX is a unique clinical trial aimed at
addressing the question as to whether or not extended
anticoagulation in high-risk patients is superior to
standard enoxaparin in terms of efficacy and safety in
this indication. Extended duration therapy with an
effective oral anticoagulant given once daily may simplify
pharmacologic prophylaxis in acutely ill medical patients
and result in a meaningful reduction in post-discharge
VTE-associated complications.

References
1. Amin AN, Varker H, Princic N, et al. Duration of venous
thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med 2012;7:231-8.
2. Samama M, Cohen AT, Darmon JY, et al. Comparison of
enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999;341(11)
793-800.
3. Leizorovicz A, Cohen AT, Turpie AGG, et al. Randomized, placebocontrolled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004;110:
874-9.

American Heart Journal

Volume 167, Number 3

4. Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of
fondaparinux for the prevention of venous thromboembolism in older
acute medical patients: randomized placebo controlled trial. Br Med J
2006;332:325-9.
5. Heit JA, Melton JM, Lohse CM, et al. Incidence of venous
thromboembolism in hospitalized patients vs. community residents.
Mayo Clin Proc 2001;76:1102-10.
6. Cohen AT. Results from the VEG Registry. Results from the VEG
Registry. International Society of Thrombosis and Haemostasis
Meeting, Kyoto Japan; 2011.
7. Hull R, Schellong SM, Tapson VF, et al. Extended-duration venous
thromboembolism prophylaxis in acutely ill medical patients with
recently reduced mobility. Ann Intern Med 2010;153:8-18.
8. Schulman S, Kearon C. Definition of major bleeding in clinical
investigations of antihemostatic medicinal products in non-surgical
patients. J Thromb Hemost 2005;3:692-4.
9. Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban for
thromboprophylaxis in acutely ill medical patients. N Engl J Med
2013;368:513-23.

Cohen et al 341

10. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus

enoxaparin for thromboprophylaxis in medically ill patients. N Engl J
Med 2011;365:2167-77.
11. Connolly S, Eikelboom J, Dorian P, et al. Betrixaban compared with
warfarin in patients with atrial fibrillation: results of a phase 2,
randomized, dose-ranging study (EXPLORE-Xa). Eur Heart J 2013;
34(20):1498-505.
12. Turpie A, Bauer KA, Davidson BL, et al. A randomized evaluation of
betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb
Haemost 2009;101:68-76.
13. Hull RD, Mareli T, Mills A, et al. LiangJ. Venous thromboembolism in
elderly high-risk medical patients: time course of events and influence
of risk factors. Clin Appl Thromb Hemost 2013;19(4):357-62.
14. Cohen AT. Results of subgroup analysis from the MAGELLAN
Study International Society of Thrombosis and Haemostasis
Meeting, Kyoto Japan; 2011.
15. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical
patients. Chest 2012;141(2 Suppl):195-226.