American Journal of Health-System Pharmacy™

Encompassing VOLUME 67 | NUMBER 10 | SUPPLEMENT 6

the full scope of MAY 15, 2010
pharmacy practice

in hospitals and

health systems

Improving anticoagulant use for prevention

of venous thromboembolism

Official journal

of the

American Society

of Health-System
Supported by an educational grant from Ortho-McNeil,
Pharmacists®
Division of Ortho-McNeil-Janssen Pharmaceuticals,
Inc., administered by Ortho-McNeil Janssen Scientific
www.ajhp.org Affairs, LLC

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 American Journal of Health-System Pharmacy™
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www.ashp.org
Official Journal
American Society of Health-System Pharmacists

Henri R. Manasse, Jr.

Executive Vice President

May 15, 2010

Copyright © 2010
American Society of Health-System Pharmacists, Inc.
Coden: AHSPEK All rights reserved.
ISSN: 1079-2082
AJHP is a federally registered trademark.

Improving anticoagulant use

for prevention of venous thromboembolism
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Articles based on the proceedings of a symposium held December 8, 2009, during the 44th ASHP
Midyear Clinical Meeting and Exhibition in Las Vegas, Nevada. This activity was supported by an
educational grant from Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.,
administrated by Ortho-McNeil Janssen Scientific Affairs, LLC.

The American Society of Health-System Pharmacists is accredited by the Accreditation

Council for Pharmacy Education as a provider of continuing pharmacy education. The
supplement as a whole provides 2.5 hours (0.25 CEU) of continuing-education credit
(ACPE activity 204-000-10-429-H01P, knowledge-based activity).

See page S31 or http://ce.ashp.org to locate the continuing-education learning objectives,

self-assessment questions, and instructions covering the articles in this supplement.

Am J Health-Syst Pharm—Vol 67 May 15, 2010 Suppl 6 S1

5b-Advantage_toc.indd 1 4/27/2010 2:54:05 PM

 SYMPOSIUM  Introduction

SYMPOSIUM

Improving anticoagulant use

for prevention of venous thromboembolism
Introduction
Stuart T. Haines
Am J Health-Syst Pharm. 2010; 67(Suppl 6):S2-3

V
enous thromboembolism (VTE)
is a common and costly cause of
morbidity and mortality in the
United States. Each year an estimated
600,000 ­Americans experience symp-
tomatic VTE.1 ­Nearly a third of these
patients will experience recurrent
VTE events over the next 10 years,
and as many as 100,000 will die from
pulmonary embolism (PE). 1 The
health care costs of VTE amount to
nearly $500 million annually in the
United States.2
VTE is preventable, yet the
­problem persists despite national
quality improvement initiatives.3-7
Reducing the frequency of VTE is
a major concern for health-system
pharmacists and administrators,
particularly because of mandatory
practice and outcomes reporting and
pay-for-­performance requirements
by accreditation and governmental
bodies.
Anticoagulants play an important
role in reducing the frequency of VTE.
Currently available agents have short-
comings that make their use prob-
lematic, especially in certain patient
populations and clinical scenarios.
Several new anticoagulants under de-
velopment offer advantages over
traditional agents, including the po-
tential to improve patient outcomes.
Health-system pharmacists have a key
role in efforts to improve anticoagu-
lant use to prevent VTE, particularly
in evaluating the place of new antico-
agulants in VTE prevention.
The first article in this supplement
describes risk factors for VTE, qual-
ity improvement efforts aimed at
VTE prevention, and strategies that
health-system pharmacists can use
to improve anticoagulant use and
outcomes in patients at risk for VTE.
In the second article, the difficul-
ties and issues associated with VTE
risk assessment and the use of drug
therapies for VTE prophylaxis are
discussed. The third article provides
an overview of the shortcomings of
currently available anticoagulants
and the characteristics of some of the
new agents demonstrated in Phase
III clinical trials. The mechanisms of
­action, pharmacokinetics, adminis-
tration, efficacy, safety, and potential
for drug interactions of emerging
anticoagulants for prevention of
VTE are described in detail. Finally,
the fourth article discusses several
clinical and management challenges
­related to the use of anticoagu-
lants for VTE prevention in health
­systems.

Stuart T. Haines, Pharm.D., BCPS, FCCP, FASHP, FAPhA, is Profes-
sor and Pharmacotherapy Specialist, University of Maryland School of
Pharmacy, Baltimore, Maryland, and Clinical Pharmacy Specialist, West
Palm Beach Veterans Affairs Medical Center, West Palm Beach, Florida.
Address correspondence to Dr. Haines at 13859 Geranium Place,
Wellington, FL 33414 (shaines@rx.maryland.edu).
Based on the proceedings of a symposium held December 8, 2009,
during the 44th ASHP Midyear Clinical Meeting and Exhibition
in Las Vegas, Nevada, and supported by an educational grant from
Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals,
Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC.
Dr. Haines reports that he has been a stockholder (<$10,000) in Merck
and that his spouse has served as a consultant for Procter & Gamble.
Dr. Haines received an honorarium from the American Society of
Health-System Pharmacists for his participation in the symposium
and for his work on this article. This article was developed with the
assistance of a medical writer working with ASHP Advantage. The
medical writer, Susan R. Dombrowski, M.S., reports that she has no
relevant financial relationship with a commercial intrest, as defined
by the Accreditation Council for Pharmacy Education. The author
approved the final article and all its content.
Copyright © 2010, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/10/0502-00S2$06.00.
DOI 10.2146/ajhp100175

S2 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6

5b-Advantage_10-0175.indd 2 4/28/2010 2:39:20 PM

 SYMPOSIUM  Improving the quality of care

References
1. U.S. Department of Health and Human
Services. The Surgeon General’s Call to
Action to Prevent Deep Vein Throm-
bosis and Pulmonary Embolism. 2008.
w w w. s u r g e o n g e n e r a l . g o v / t o p i c s /
deepvein/calltoaction/call-to-action-
on-dvt-2008.pdf (accessed 2010 Jan 8).
2. Hawkins D. Pharmacoeconomics of
thrombosis management. Pharmaco-
therapy. 2004; 24(7 pt 2):95S-99S.
3. Geerts WH, Bergqvist D, Pineo GF et al.
Prevention of venous thromboembo-
lism: American College of Chest Physi-
cians evidence-based clinical practice
guidelines (8th edition). Chest. 2008;
133(6 Suppl):381S-453S.
4. Agency for Healthcare Research and Qual-
ity. Preventing hospital-acquired venous
thromboembolism: a guide for effec-
tive quality improvement. August 2008.
www.ahrq.gov/qual/vtguide/vtguide.pdf
­(accessed 2009 Dec 11).
5. Lyman GH, Khorana AA, Falanga A
et al. American Society of Clinical
Oncolog y guideline: recommenda-
tions for venous thromboembolism
prophylaxis and treatment in patients
with cancer. J Clin Oncol. 2007; 25:
5490-505.
6. American College of Obstetricians and
Gynecologists Committee on Practice
Bulletins. ACOG Practice Bulletin No. 84:
Prevention of deep vein thrombosis and
pulmonary embolism. Obstet Gynecol.
2007; 110(2 Pt 1):429-40.
7. American Academy of Orthopaedic
­Surgeons. Clinical guideline on pulmo-
nary embolism in patients undergoing
total hip or knee arthroplasty. May 2007.
www.aaos.org/Research/guidelines/PE_
guideline.pdf (accessed 2009 Dec 11).

Improving the quality of care for patients at risk

for venous thromboembolism
Stuart T. Haines

R
udolf Virchow, a 19th cen-
tury German physician and
physiologist, described the three
main types of abnormalities that
can result in thrombus (clot) for-
mation in blood vessels: endothe-
lial injury, circulatory stasis, and
hypercoagulable states. These three
abnormalities—known as Virchow’s
triad—are the fundamental causes of
venous thromboembolism (VTE).1
Virchow understood that injury to
the vascular endothelium (i.e., lining
of the inner wall of blood vessels)
through trauma, surgery, or inser-
tion of a catheter provokes a cascade
of events, including fibrin formation
and platelet adhesion, and results in
clot formation. He also recognized
Purpose. To describe risk factors for venous
thromboembolism (VTE), quality improve-
ment efforts for VTE prevention, and strate-
gies health-system pharmacists can use to
improve anticoagulant use and outcomes
in patients at risk for VTE.
Summary. Risk factors for VTE involve
the presence of one or more components
of Virchow’s triad (endothelial injury,
circulatory stasis, and hypercoagulable
states) and are exceedingly common in
hospitalized ­p atients. Several effective
methods for VTE prophylaxis are read-
ily available but remain underused. Qual-
ity improvement initiatives to improve VTE
prophylaxis rates include evidence-based
clinical practice guidelines, mandatory
practice and outcomes reporting, and pay-
for-performance requirements. The devel-
opment and implementation of VTE risk as-
sessment tools and treatment algorithms,
protocols, policies, and procedures are
among the strategies that health-system
pharmacists can use to improve anticoagu-
lant use and quality of care in patients at
risk for VTE.
Conclusion. The use of anticoagulant ther-
apy presents health-system pharmacists
with both challenges and opportunities to
improve the quality of care in patients at
risk for VTE.
Index terms: Anticoagulants; Hospitals;
Patient care; Pharmacists, hospital; Proto-
cols; Quality assurance; Risk management;
Venous thromboembolism
Am J Health-Syst Pharm. 2010; 67(Suppl
6):S3-8

Stuart T. Haines, Pharm.D., BCPS, FCCP, FASHP, FAPhA, is Profes-
sor and Pharmacotherapy Specialist, University of Maryland School
of Pharmacy, Baltimore, Maryland, and Clinical Pharmacy Specialist,
West Palm Beach Veterans Affairs Medical Center, West Palm Beach,
Florida.
Address correspondence to Dr. Haines at 13859 Geranium Place,
Wellington, FL 33414 (shaines@rx.maryland.edu).
Based on the proceedings of a symposium held December 8,
2009, during the 44th ASHP Midyear Clinical Meeting and Exhibi-
tion in Las Vegas, Nevada, and supported by an educational grant
from Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharma-
ceuticals, Inc., administered by Ortho-McNeil Janssen Scientific
Affairs, LLC. Dr. Haines reports that he has been a stockholder
(<$10,000) in Merck and that his spouse has served as a consultant
for Procter & Gamble. Dr. Haines received an honorarium from the
American Society of Health-System Pharmacists for his participa-
tion in the symposium and for his work on this article. This article
was developed with the assistance of a medical writer working
with ASHP Advantage. The medical writer, Susan R. Dombrowski,
M.S., reports that she has no relevant financial relationaship with
a commercial interest, as defined by the Accreditation Council for
Pharmacy Education. The author approved the final article and all
its content.
Copyright © 2010, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/10/0502-00S3$06.00.
DOI 10.2416/ajhp100176

Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6 S3

5b-Advantage_10-0175.indd 3 4/27/2010 2:54:53 PM

 SYMPOSIUM  Improving the quality of care
that clots are more likely to form in
slow-moving blood than in blood
that flows swiftly. The forces (i.e.,
pressures) that propel blood and the
rate of blood flow are much lower
in the veins than in the arteries, so
spontaneous clot formation is more
likely in the veins than in the arteries.
A near cessation in blood flow (i.e.,
stasis) alone can provoke clot forma-
tion. Circulatory stasis and clots can
occur during prolonged periods of
immobility (e.g., in elderly patients
or air travelers).
Virchow also was aware that some
people are more or less prone to
clot formation than others because
of hereditary deficiencies or genetic
mutations (e.g., people with hemo-
philia have a reduced tendency to clot
because of a deficiency of clotting
factor VIII or IX). Clot formation is
associated with numerous hyperco-
agulable states (i.e., thrombophilias)
characterized by excessive amounts
of procoagulant substances in the
circulation or deficiencies of en-
dogenous anticoagulants caused by
Table 1.
Risk Factors for VTE6,7,a
Major Risk Factors
Major surgery (especially involving the hip, knee, or abdomen)
Major trauma
Malignancy (especially metastatic disease)
Major medical illness (e.g., CHF, MI, sepsis)
Prolonged immobility (≥ 3 days)
Previous DVT/PE
Increasing age (> 40 yr)
Contributing Risk Factors
Thrombophilia/hypercoagulable states
Antithrombin III deficiency
Protein C or S deficiency
Activated protein C resistance/Factor V Leiden
Prothrombin (20210) gene mutation
Antiphospholipid antibodies
Use of estrogens/raloxifene/tamoxifen
Pregnancy/early post-partum period
Obesity
CHF = congestive heart failure; DVT = deep vein thrombosis; MI = myocardial infarction; PE = pulmonary
embolism; VTE = venous thromboembolism
a
This list is not inclusive.
S4 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
5b-Advantage_10-0176.indd 4
heredity, genetic mutations, acquired
diseases, or malignancy.
Virchow understood the role
that the three phenomena—vessel
injury, blood stasis, and circulating
factors—play in the development
and propagation of clots. He reached
this understanding without the ben-
efit of electron microscopes, mass
spectrometry, or enzyme-linked
immunosorbent assay. Today’s clini-
cians can still use Virchow’s triad to
identify patients at risk.
Identifying patients at risk
Most hospitalized patients are at
risk for VTE, but VTE prophylaxis is
underutilized.2-5 Table 1 lists the ma-
jor risk factors for VTE, and these risk
factors reflect the presence of one or
more components of Virchow’s triad.
For example, patients undergoing
major surgery experience endothelial
injury and are immobilized during
and after the procedure. Patients
undergoing orthopedic procedures
involving a hip or knee are often inac-
tive for several days during a postop-
erative recovery period. Major trauma
from a motor vehicle accident or
gunshot results in endothelial injury;
surgical repair often is required, with
additional endothelial injury and im-
mobilization during the procedure
and recovery period.
Patients with malignancy, a com-
mon cause of hospitalization, are
in a hypercoagulable state. Some
malignancies (e.g., brain tumors;
adenocarcinomas of the lung, ovary,
pancreas, colon, stomach, prostate,
and kidney; and hematologic malig-
nancies) are associated with a greater
risk for VTE than are others.6 More-
over, many cancer patients require
surgery, have indwelling catheters in
place, and are frail and immobilized.
The risk for VTE is particularly high
in patients who have metastatic dis-
ease and are receiving chemotherapy.
Many patients with major medical
illness (e.g., congestive heart fail-
ure, respiratory failure, myocardial
infarction, sepsis) are hospitalized.
Venous stasis may develop during
their hospitalization.
Increasing age is an indepen-
dent risk factor for VTE.6 Hospital-
ized medical and surgical patients
typically are more than 40  years of
age, and advanced age adds to the
risk for VTE associated with major
medical illness and surgery.
A history of deep vein thrombo-
sis (DVT) or pulmonary embolism
(PE) often reflects the presence of
a hypercoagulable state that places
patients at high risk for recurrence.6
DVT in the lower legs can damage
the venous valves and slow the rate
of return blood flow to the heart or
can result in retrograde flow in the
affected vein. Partial venous obstruc-
tion from the initial clot may persist,
predisposing the patient to recurrent
thrombus formation.
Various contributing risk factors
for VTE (Table  1) may be present
in hospitalized patients.7 Inherited
or acquired hypercoagulable states
are among the risk factors that may
be present in hospitalized patients.6
4/27/2010 2:55:53 PM

The most common, factor V Leiden,
is a genetic abnormality in coagula-
tion factor V that leads to activated
protein C resistance (i.e., failure of
the natural anticoagulant protein C
to regulate clotting activity of factor
V). An acquired hypercoagulable
state commonly associated with au-
toimmune disorders (e.g., systemic
lupus erythematosus, rheumatoid
arthritis, Crohn’s disease) is the pres-
ence of antiphospholipid antibodies.
Medications with estrogenic activity,
including estrogen-containing oral
contraceptive tablets and skin patches,
estrogen-replacement therapy, and
vaginal contraceptive rings that
contain estrogen, as well as estrogen
agonist–antagonists (i.e., selective
estrogen receptor modulators), can
provoke clot formation.6 The mecha-
nism is not entirely understood,
but estrogens are believed to in-
duce a hypercoagulable state in a
dose-dependent manner. Pregnancy
and the early postpartum period
also are associated with an increased
risk for VTE, presumably because of
the high levels of estrogen present at
those times.
Obesity increases the risk for
VTE, possibly from circulatory stasis
caused by pressure from excessive
body weight on the leg veins and
reduced venous return from the
lower extremities.6 The effect of obe-
sity also could be indirect through
diminished physical activity and an
increased risk for medical illnesses
that predispose patients to VTE (e.g.,
heart failure, osteoarthritis requiring
joint replacement surgery).
Quality of care
Emphasis on the quality of patient
care has increased over the years, and
the use of practice guidelines and
quality measures has moved from
voluntary to mandatory. Numerous
clinical studies over the past several
decades have evaluated the efficacy of
various nonpharmacologic and phar-
macologic interventions for prevent-
ing VTE. In the mid to late 1980s, var-
5b-Advantage_10-0176.indd 5
SYMPOSIUM  Improving the quality of care
ious organizations used the findings
of these studies to develop evidence-
based clinical practice guidelines for
prophylactic therapy in patients at
risk for VTE. As clinicians’ acceptance
of these guidelines increased, con-
sensus standards of practice for pro-
viding patient care were developed.
Organizations devoted to quality
improvement began promulgating
the use of quality measures to ensure
that standards of practice were met
and to assess hospital and physician
performance and patient outcomes.
Over the past four or five years, it has
become mandatory to report these
quality measures for comparison
among practitioners and facilities
and identification of those with
exemplary performance. Recently,
pay-for-performance requirements
have been established, with quality
goals and financial incentives and re-
wards for meeting those goals.
Perhaps the best known evidence-
based clinical practice guidelines for
VTE prevention are those published
by the American College of Chest
Physicians (ACCP) as part of a set
of guidelines regarding the use of
antithrombotic and thrombolytic
therapy.6 These guidelines are up-
dated periodically and released as a
supplement to the periodical Chest;
the most recent (8th) edition was
published in June 2008. The 2008
ACCP guideline for VTE prevention
is very comprehensive—72 pages
long, with 89 recommendations and
728 references. The ACCP guidelines
are authoritative and provide a basis
for many of the guidelines and qual-
ity improvement initiatives of other
organizations.
In August 2008, the Agency for
Healthcare Research and Quality
(AHRQ), a governmental organiza-
tion, released Preventing Hospital-
Acquired Venous Thromboembolism:
A Guide for Effective Quality Improve-
ment.8 This publication relies heavily
on the ACCP guidelines, but it also
addresses systems of care that should
be implemented in hospitals.
Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
Other evidence-based clinical
practice guidelines focus on specific
patient populations at risk for VTE.
For example, guidelines for VTE pre-
vention in patients with cancer are
available from the American Society
of Clinical Oncology, and guidelines
for women during pregnancy or the
early postpartum period are available
from the American College of Obste-
tricians and Gynecologists.9,10
The American Academy of
Orthopaedic Surgeons (AAOS) Clini-
cal Guideline on Pulmonary Embolism
in Patients Undergoing Total Hip Or
Knee Arthroplasty is available on the
organization’s website, but it has not
been published in a peer-reviewed
journal.11 The AAOS document is
controversial; it contains recommen-
dations for the use of aspirin to pre-
vent PE in orthopedic surgery that are
not consistent with the ACCP guide-
lines. The ACCP guidelines recom-
mend against the use of aspirin alone
for VTE prevention in these patients.6
Clinical practice guidelines require
the interpretation of evidence. The
recommendations and conclusions
drawn from the evidence may differ
depending on the experience and
values of the individuals writing the
guidelines. Discrepancies among
guidelines from different sources
often reflect conflicting opinions
among experts.
The clinical studies that are the
source of evidence-based guidelines
often have stringent patient inclusion
and exclusion criteria. Extrapolation
of the results of clinical studies to pa-
tient populations that did not meet
the inclusion criteria is inappropri-
ate, but clinicians often must make
well-reasoned inferences when data
regarding the best course of action
are lacking.
The processes used to develop and
publish evidence-based guidelines
are time-consuming, often requiring
years. By the time guidelines are pub-
lished, they may not reflect current
data. Nevertheless, evidence-based
guidelines for VTE prophylaxis are
S5
4/27/2010 2:56:02 PM
 SYMPOSIUM  Improving the quality of care

valuable tools for ensuring quality core performance measures pertain American Hospital Association, Vet-
care. to VTE (Table  2).13 The incidence of erans Health Administration, and
AHRQ has identified and ranked VTE during or within 30 days after Premier, Inc.15 Participation in SCIP
10 safety practices on the basis of the a hospital stay that could have been involves collecting and submitting
strength of evidence.12 Appropriate avoided by using prophylaxis is among quality data, sharing best practices
VTE prophylaxis in patients at risk is the data reported by hospitals. and implementation strategies, and
ranked first on this list of the safety The Surgical Care Improvement making system changes based on
practices that can have the greatest Project (SCIP) is a national initiative quality improvement data. Two SCIP
impact on patient care. developed by the Centers for Medi- process measures have been estab-
National quality improvement care and Medicaid Services (CMS), lished for ordering and administering
initiatives have been developed by Centers for Disease Control and Pre- VTE prophylaxis, and two proposed
various organizations to drive efforts vention, and various organizations, SCIP outcome measures include
to improve the care of patients at with a goal of reducing postoperative reporting the incidence of DVT and
risk for VTE. The Joint Commis- complications by 25% before 2010.14 PE during hospitalization or within
sion and National Quality Forum The initiative represents the efforts 30 days after surgery (Table 3).13
outlined core performance measures of a coalition of major public and In October 2008, CMS discon-
that hospitals are required to report, private health groups, including tinued payment for certain costly,
which facilitates quality comparisons the American Medical Association, avoidable secondary diagnoses that
among institutions. Several of the American College of Surgeons, result from hospitalization and
cause serious injury or death. 16
CMS considers VTE after total hip
or knee replacement surgery one of
Table 2.
these avoidable “never events.”16 Es-
Joint Commission and National Quality Forum Core Performance
tablishing these outcomes as “never
Measures Pertaining to VTE Prophylaxis13,a
events” without reimbursement is an
VTE Core Performance Measures application of pay-for performance
Risk assessment and prophylaxis requirements.
1. Documentation of VTE prophylaxis given or why no prophylaxis was given Anticoagulant medications play
within 24 hours of hospital admission a central role in preventing VTE,
2. Documentation of VTE prophylaxis given or why no prophylaxis was given but the drugs are a common cause
within 24 hours of admission or transfer to ICU of adverse events because of their
VTE outcomes narrow therapeutic index, complex
6. Incidence of potentially preventable hospital-acquired VTE dosing, need for laboratory moni-
Stroke Core Performance Measures toring, and inappropriate medica-
Prophylaxis tion use behaviors by patients (e.g.,
1. Documentation of VTE prophylaxis within 24 hours of hospital admission sporadic adherence, failure to keep
a
ICU = intensive care unit; VTE = venous thromboembolism. follow-up appointments, dietary
indiscretions).17 Anticoagulants pres-
ent a patient management challenge
in hospitals, and anticoagulant thera-
Table 3.
py practices are poorly standardized.
SCIP Process and Outcome Measures for VTE13,a
Reducing the likelihood of patient
Process Measures
harm from the use of these drugs is
SCIP VTE-1. Ordered appropriate VTE prophylaxis any time from hospital arrival to a Joint Commission National Patient
24 hours after anesthesia end time Safety Goal (NPSG.03.05.01). 17,18
SCIP VTE-2. Received appropriate VTE prophylaxis within 24 hours prior to anesthesia This NPSG was phased in gradually
start time to 24 hours after anesthesia end time for full implementation by January
Outcome Measures (proposed)
1, 2009, but many hospitals had dif-
SCIP VTE-3. Intra- or post-operative PE diagnosed during index hospitalization and ficulty meeting that deadline. 19,20
within 30 days of surgery Therefore, the Joint Commission has
SCIP VTE-4. Intra- or post-operative DVT diagnosed during index hospitalization and clarified and simplified its require-
within 30 days of surgery ments for the NPSG.20 Evaluating
a
DVT = deep vein thrombosis; PE = pulmonary embolism; SCIP = Surgical Care Improvement Project;
anticoagulation safety practices is a
VTE = venous thromboembolism. Joint Commission requirement that

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5b-Advantage_10-0176.indd 6 4/27/2010 2:56:11 PM


remains a top priority because of its
direct impact on patient outcomes.
Other requirements are impor-
tant (e.g., the use of oral unit dose
products, prefilled syringes, and
premixed infusion bags; obtaining
a baseline international normalized
ratio prior to initiating warfarin
therapy; educating prescribers, staff,
patients, and family members), but
continual efforts aimed at evaluating
and implementing institutionwide
anticoagulation safety practices will
likely have the greatest impact on
patient outcomes.
Closing the gap
The culture of medicine has
undergone a gradual evolution over
the past several decades.21 In the mid-
20th century, health care typically
was provided by individuals in solo
practices who were autonomous and
made decisions on the basis of their
knowledge and experience. These
individuals carried considerable
responsibility and were expected to
be infallible, but continuous learning
was required to stay abreast of new
developments in medicine.
Modern 21st-century medical
care is characterized by group prac-
tices in which teamwork with input
from members of various health
care professions is used for prob-
lem solving and continuous qual-
ity improvement. The burden of
decision-making is shared, because it
is understood that no one is infallible.
Modern medicine is a dynamic field,
with rapid changes brought about by
the introduction of new information
and technologies.
An appreciation of the limita-
tions of 20th-century medicine and
the need for alternative approaches
to improve the quality of care and
patient outcomes in the 21st cen-
tury provides impetus for identifying
strategies for changing the health
care culture. These strategies may
include obtaining support from
institutional management and estab-
lishing interprofessional teams. This
5b-Advantage_10-0176.indd 7
SYMPOSIUM  Improving the quality of care
approach reduces the isolation that
all too often inhibits potentially valu-
able input for solving problems and
improving clinical practices. Health-
system pharmacists in collaboration
with other members of the health
care team can play an important
role in creating cultural changes and
improving VTE prophylaxis prac-
tices. Developing hospitalwide or
unit-specific treatment algorithms or
protocols, policies, and procedures
for anticoagulant use is an impor-
tant undertaking. Topics that may
be addressed include anticoagu-
lant selection (i.e., indications for
use), dosing, duration of therapy,
laboratory and clinical monitor-
ing, adverse event management,
transition care (e.g., at the time of
transfer from an intensive care unit
to a medical floor), and hospital
discharge planning. Standardized
order sets for anticoagulants should
be developed.
In order to achieve measurable and
meaningful improvements in quality,
multiple strategies will be needed,
including creating useful tools, edu-
cating practitioners, and providing
performance feedback. Several stud-
ies have shown that VTE prophylaxis
rates improved at institutions that
developed and consistently used VTE
risk assessment tools and admission
order sets. These tools can be paper-
based or automated through the use
of informatics (e.g., electronic risk-
scoring systems with alert capabili-
ties to identify high-risk patients, and
computerized physician order entry
programs with standardized orders
and links to treatment guidelines,
algorithms, and protocols).22-25
The implementation of VTE risk
assessment tools and treatment
algorithms, protocols, policies, and
procedures requires a comprehen-
sive educational program for health
care practitioners, patients, and
family members. Health care prac-
titioners should be informed about
the rationale for and the logistics
of using any new tool or procedure.
Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
Inservice education programs and
electronic or print newsletters are
possible methods for educating
staff.
Quality metrics should be devel-
oped and data collected in order to
assess institutional performance as
well as provide ongoing feedback to
practitioners and teams. This feed-
back can be used to identify weak-
nesses and opportunities for quality
improvement.
Conclusion
Historically, implementing changes
to improve the quality of care has
been a slow process. Quality im-
provement initiatives, mandated
practice and outcomes reporting,
and pay-for-performance require-
ments for VTE prophylaxis demand
the attention of health-system phar-
macists. The challenges associated
with fulfilling these requirements
represent an opportunity for health-
system pharmacists to collaborate
with other members of the health
care team to improve the use of anti-
coagulants and the quality of care in
patients at risk for VTE.
References
1. Virchow R. Ueber die Erweiterung
kleinerer Gefäfse. Arch Pathol Anat
Physiol Klin Med. 1851; 3:427-62.
2. Aujesky D, Guignard E, Pannatier A
et  al. Pharmacological thromboembolic
prophylaxis in a medical ward: room for
improvement. J Gen Intern Med. 2002;
17:788-91.
3. Amin A, Stemkowski S, Lin J et  al.
Thromboprophylaxis rates in US medi-
cal centers: success or failure? J Thromb
Haemost. 2007; 5:1610-6.
4. Arnold DM, Kahn SR, Shrier I. Missed
opportunities for prevention of venous
thromboembolism: an evaluation of the
use of thromboprophylaxis guidelines.
Chest. 2001; 120:1964-71.
5. Yu HT, Dylan ML, Lin J et  al. Hospitals’
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6. Geerts WH, Bergqvist D, Pineo GF et al.
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American College of Chest Physicians
evidence-based clinical practice guide-
lines (8th edition). Chest. 2008; 133(6
Suppl):381S-453S.
7. Francis CW. Clinical practice. Prophy-
laxis for thromboembolism in hospital-
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ized medical patients. N Engl J Med. 2007;
356:1438-44.
8. Agency for Healthcare Research and
Quality. Preventing hospital-acquired
venous thromboembolism: a guide for
effective quality improvement. August
2008. www.ahrq.gov/qual/vtguide/
vtguide.pdf (accessed 2009 Dec 11).
9. Lyman GH, Khorana AA, Falanga A et al.
American Society of Clinical Oncology
guideline: recommendations for venous
thromboembolism prophylaxis and treat-
ment in patients with cancer. J Clin Oncol.
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10. American College of Obstetricians and
Gynecologists Committee on Practice
Bulletins. ACOG Practice Bulletin No. 84:
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pulmonary embolism. Obstet Gynecol.
2007; 110(2 Pt 1):429-40.
11. American Academy of Orthopaedic
Surgeons. Clinical guideline on pul-
monary embolism in patients under-
going total hip or knee arthroplasty.
May 2007. www.aaos.org/Research/
guidelines/PE_guideline.pdf (accessed
2009 Dec  11).
12. Agency for Healthcare Research and
Quality. Making health care safer: a
critical analysis of patient safety practices.
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(accessed 2009 Dec 11).
13. The Joint Commission. Specifications
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jointcommission.org/PerformanceMea
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Current+NHQM+Manual.htm (accessed
2009 Dec 11).
14. Miller A, Roche LM. Surgical Care
Improvement Project: from SIP to
SCIP. November/December 2007. www.
medicarepatientmanagement.com/
issues/02-06/mpmND07-SurgicalMiller.
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15. Surgical Care Improvement Project core
measure set. November 2008. www.
jointcommission.org/Performance
Measurement/PerformanceMeasurement/
SCIP+Core+Measure+Set.htm (accessed
2009 Dec 11).
16. Centers for Medicare & Medicaid Services.
Medicare and Medicaid move aggressively
to encourage greater patient safety in hos-
pitals and reduce never events. July 31, 2008.
www.cms.hhs.gov/apps/media/press/
release.asp?Counter=3219&intNumPer
Page=10&checkDate=&checkKey=&
srchType=1&numDays=3500&srchOpt=
0&srchData=&keywordType=All&chkN
ewsType=1%2C+2%2C+3%2C+4%2C+
5&intPage=&showAll=&pYear=&year=
&desc=false&cboOrder=date (accessed
2009 Dec 12).
17. The Joint Commission. Accreditation
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(accessed 2009 Dec 11).
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JCP-07-08-S1.pdf (accessed 2009 Dec
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19. The Joint Commission. Preventing
errors relating to commonly used an-
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PressKits/Preventing+Errors+Relating+
to+Commonly+Used+Anticoagulants/
applicable_standards.htm (accessed 2009
Dec 12).
20. Rich DS. Update on the implementation
of the Joint Commission anticoagulation
National Patient Safety Goal. Presented
at the ASHP Midyear Clinical Meeting
and Exhibition; Rosemont, IL: June 15,
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A n t i c o a g u l a t i o n / S M 0 9 _ Na t i o n a l
_Patient_Safety_Goal_Anticoag.pdf
(accessed 2009 Dec 12).
21. Shine KI. Health care quality and how to
achieve it. Acad Med. 2002; 77:91-9.
22. Dobesh PP, Stacy ZA. Effect of a clini-
cal pharmacy education program on
improvement in the quantity and quality
of venous thromboembolism prophylaxis
for medically ill patients. J Manag Care
Pharm. 2005; 11:755-62.
23. Piazza G, Rosenbaum EJ, Pendergast W
et  al. Physician alerts to prevent symp-
tomatic venous thromboembolism in
hospitalized patients. Circulation. 2009;
119:2196-201.
24. Kucher N, Koo S, Quiroz R et al. Electron-
ic alerts to prevent venous thromboem-
bolism among hospitalized patients. N
Engl J Med. 2005; 352: 969-77.
25. Tooher R, Middleton P, Pham C et  al. A
systematic review of strategies to improve
prophylaxis for venous thromboembolism
in hospitals. Ann Surg. 2005; 241:397-415.
4/28/2010 2:41:01 PM
 SYMPOSIUM  Assessing and reducing the risk

Issues in assessing and reducing the risk

for venous thromboembolism
William E. Dager

V
enous thromboembolism (VTE)
prophylaxis is underutilized in
the United States despite the
availability of evidence-based clinical
practice guidelines from authorita-
tive sources.1-8 Many reported cases
of VTE occur in patients with related,
yet unrecognized, risk factors who
did not receive prophylaxis when it
was indicated. Rates of adherence to
guidelines for VTE prophylaxis of
less than 20% have been reported.4
Failure to adhere to clinical prac-
tice guidelines could lead to several
undesirable situations. Patients at
risk for VTE are a heterogeneous
group, receiving care on both an
inpatient and an outpatient basis
for a variety of conditions that cross
many medical disciplines. Preventing
VTE seldom is the responsibility of
any one specialist. Clinicians often
are not focused on risk for VTE, and
assessing the risk can be perceived
as complex and laborious. Clinical
research has been inadequate to fully
define the patient populations at
risk and the drugs and dosing strat-
egies that are best used in selected
Purpose. To describe issues and challenges
associated with venous thromboembolism
(VTE) risk assessment and the use of drug
therapies for VTE prophylaxis.
Summary. Patients at risk for VTE are a
heterogeneous group. Systems for scoring
VTE risk have been developed to iden-
tify patients who warrant prophylaxis, but
most risk-scoring systems are complex and
have not been validated. The optimal drug
therapies and dosing strategies for reduc-
ing VTE risk are not well defined for many
clinical situations, despite the availability of
evidence-based guidelines from authorita-
tive sources. Patient characteristics can in-
fluence the agent selected, dosing, timing
of initiation, and duration of drug therapy.
Individualized approaches to prophylaxis
in patients undergoing major orthopedic
surgery should take into account the pres-
ence of severe renal impairment, critical
situations to reduce the risk. A lack
of consensus and standardization
of the methods for measuring and
defining outcomes in clinical tri-
als is part of the problem. Several
methods (e.g., venography, Doppler
ultrasonography) are currently avail-
illness, morbid obesity, epidural catheters,
and history of heparin-induced thrombo-
cytopenia. To provide safe, effective VTE
prophylaxis, clinicians, including health-
system pharmacists, should collaborate in
developing management plans tailored to
patients’ needs.
Conclusion. Preventing VTE is a challenge
that can be addressed by gaining an under-
standing of the issues involved in patient
assessment and prophylactic drug therapy
and using a team approach to optimize
patient outcomes.
Index terms: Anticoagulants; Dosage;
Drugs; Heparin; Hospitals; Pharmacists,
hospital; Protocols; Risk management;
Team; Thrombocytopenia; Toxicity; Venous
thromboembolism
Am J Health-Syst Pharm. 2010; 67(Suppl
6):S9-16
able for detecting deep vein throm-
bosis (DVT). Venography, which
is generally considered the gold
standard, is a complex procedure.9
Definitions and outcomes related
to bleeding in clinical trials, includ-
ing what constitutes minor, major,

William E. Dager, Pharm.D., Bcps, Fcshp, Fccp, Fccm, is
Pharmacist Specialist, University of California Davis Medical Cen-
ter; Clinical Professor of Pharmacy, University of California, San
Francisco, and Touro School of Pharmacy; and Clinical Professor of
Medicine, ­University of California, Davis, Sacramento, California.
Address correspondence to Dr. Dager at UC Davis Medical Cen-
ter, 2315 Stockton Blvd., Sacramento, CA 95817 (william.dager@
ucdmc.ucdavis.edu).
Based on the proceedings of a symposium held December 8, 2009,
during the 44th ASHP Midyear Clinical Meeting and Exhibition in Las
Vegas, Nevada, and supported by an educational grant from Ortho-
McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., ad-
ministered by Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Dager
has disclosed no relevant financial relationship with a commercial inter-
est, as defined by the Accreditation Council for Pharmacy Education
(ACPE). Dr. Dager received an honorarium from the American Society
of Health-System Pharmacists for his participation in the symposium
and for his work on this article. This article was developed with the assis-
tance of a medical writer working with ASHP Advantage. The medical
writer, Susan R. Dombrowski, M.S., reports that she has no relevant
financial relationaship with a commercial interest, as defined by
ACPE. The author approved the final article and all its content.
Copyright © 2010, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/10/0502-00S9$06.00.
DOI 10.2146/ajhp100177

Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6 S9

5b-Advantage_10-0177.indd 9 4/28/2010 3:07:39 PM

 SYMPOSIUM  Assessing and reducing the risk

or life-threatening events will differ VTE or have multiple risk factors ma, burns, or medical illness (acute
between trials, making it difficult to for VTE or a high risk for bleeding.5 medical illness, cancer, critical care)
cross compare trial observations for Bleeding is a particularly important and long-distance travelers also are
a particular agent or agents. concern after surgery, since pharma- within the scope of the ACCP guide-
The American College of Chest cologic interventions to prevent VTE lines. The types of interventions out-
Physicians (ACCP) updated its increase the risk for oozing or bleed- lined in the ACCP guidelines include
evidence-based clinical practice ing at the surgical site. graduated compression stockings
guidelines for VTE prevention in Orthopedic surgeries specifically (GCS), intermittent pneumatic com-
2008.5 Recommendations for VTE addressed by the ACCP guidelines pression (IPC), unfractionated hepa-
prophylaxis are provided in these include procedures for total hip and rin (UFH), low molecular weight
guidelines for patients undergoing knee replacement, knee arthroscopy, heparin (LMWH), the indirect factor
various types of surgery, including hip fracture, and spinal cord injury. Xa inhibitor fondaparinux, and vita-
vascular, gynecologic, urologic, lap- Patients undergoing total hip or knee min K antagonists (e.g., warfarin).
aroscopic, bariatric, thoracic, coro- replacement or hip fracture surgery Determining which patients
nary artery bypass, neurosurgery, are well studied, because the large ­require VTE prophylaxis involves a
general, and orthopedic surgery. number of Americans who undergo risk factor assessment (Table 1), for
General surgery patients are clas- these procedures every year have which a risk-scoring system may be
sified on the basis of whether they a high risk for VTE and associated used.11-14 Such systems assign points
are at low, moderate, or high risk for health care costs.10 Patients with trau- to each VTE risk factor (usually
weighted on the basis of the contri-
bution of the factor to VTE risk),
and prophylaxis is indicated for a
Table 1. patient if the sum of the points for
Risk Factors for VTE Commonly Used in Risk Scoring Systems11-14 all of his or her risk factors exceeds a
threshold.12,13 The threshold reflects
Advanced age
History of VTE
the level beyond which the risk is
Malignancy unacceptably high without pharma-
Congestive heart failure cologic prophylaxis. Most of these
Respiratory disease/chronic obstructive pulmonary disease risk-scoring systems are complex to
Obesity (BMI >30 kg/m2) use, have not been validated, and do
Prolonged immobility/length of stay ≥ 3 days not take into consideration bleeding
Surgery/trauma risk, although a model for predicting
Stroke cancer chemotherapy-related VTE
Acute medical illness recently was validated.13 The opt-out
Inflammatory bowel disease (Crohn’s disease/ulcerative colitis)
approach involves the automatic or-
Hypercoagulable states
dering of VTE prophylaxis unless a
BMI = body mass index; VTE = venous thromboembolism condition exists suggesting that pro-
phylaxis is unnecessary or potentially
harmful (Table 2).
Table 2. Requirements for VTE prophy-
Criteria for Opting Out of VTE Prophylaxis at the University of laxis can change during the course of
California Davis Medical Center hospitalization and after discharge.
Therefore, the need for prophylaxis
Imminent invasive procedure should be reassessed periodically.
Use of warfarin with INR > 1.4 or on therapeutic anticoagulation
Recent intraocular or intracranial surgery
Initiating prophylaxis
Thrombocytopenia
Spinal tap or epidural anesthesia anticipated within 12 hr The initiation of VTE prophylaxis
Active bleeding is a challenge for clinicians, espe-
Active or chronic severe liver disease cially when prophylaxis is needed
Receiving comfort care for surgical patients. The Surgical
Healthy, fully ambulatory, and < 40 years old Care Improvement Project (SCIP)
History of HIT/hypersensitivity to UFH or LMWH is a national quality improvement
HIT = heparin-induced thrombocytopenia; INR = international normalized ratio; LMWH = low molecular initiative developed by the Centers
weight heparin; UFH = unfractionated heparin; VTE = venous thromboembolism for Medicare and Medicaid Services

S10 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6

5b-Advantage_10-0177.indd 10 4/28/2010 3:08:20 PM


(CMS) and various organizations to
reduce postoperative complications.
Receiving appropriate VTE prophy-
laxis in the period between 24 hours
before the anesthesia start time and
24  hours after the anesthesia end
time is a required SCIP process mea-
sure.15 Multiple transfers, from the
operating room to recovery and ulti-
mately to the ward, can create delays
in the initiation of therapy. Perfor-
mance can be improved by having
systems in place, such as electronic
alerts about the need to administer
VTE prophylaxis within this 24-hour
window after surgery.
Considerations in planning or
evaluating the appropriateness of
VTE prophylaxis during the 24-hour
period after surgery include whether
heparin was used preoperatively
and what therapy might have been
used in the postanesthesia care unit
and surgical care unit. Mechanical
thromboprophylaxis (i.e., GCS or
IPC) is an option for many patients
at high risk for bleeding, but adher-
ence to IPC is low.5
The use of combination anti-
coagulant therapy (e.g., injectable
heparin during warfarin initiation)
may be a better choice than heparin
alone to  provide adequate postop-
erative VTE prophylaxis in orthope-
dic surgery patients, although this
approach to postoperative VTE pro-
phylaxis is not evidence based. The
presence of an epidural catheter for
administration of analgesics may be
a consideration in the initiation of
warfarin because of concerns about
bleeding and spinal hematoma for-
mation, a rare but potentially devas-
tating complication. In some cases,
a rapid rise in the international
normalized ratio (INR) from initial
factor VII loss may lead to INR val-
ues above 2 within 24 hours. For this
reason, clinicians may prefer to wait
until the epidural catheter has been
­removed before starting ­warfarin.5
The use of peripheral nerve blocks
does not seem to warrant the same
level of concern.
5b-Advantage_10-0177.indd 11
SYMPOSIUM  Assessing and reducing the risk
The need for and risks associated
with VTE prophylaxis in orthopedic
surgery patients (i.e., the risks for
bleeding and thrombosis) change
over time and depend on the type of
orthopedic surgery. The risk for DVT
and bleeding is initially higher after
knee replacement surgery than after
hip replacement surgery.5 However,
the risk for pulmonary embolism
(PE) is higher after hip surgery than
knee surgery, possibly because of the
proximity of the hip to the lungs.5
Duration of prophylaxis
The duration of VTE prophylaxis
needed may depend on the period of
VTE risk benefiting from prevention.
This can be influenced by patient
characteristics (e.g., prolonged im-
mobility) and differs among medi-
cal patients and surgical patients
and different types of surgeries. For
example, older, obese patients may
require additional prophylaxis after
surgery. In a retrospective study of
orthopedic patients with VTE despite
prophylaxis, the median time to VTE
diagnosis was significantly longer
after total hip replacement surgery
(17 days) than after total knee replace-
ment surgery (7 days, p < 0.001).16 A
longer duration of VTE prophylaxis
(six weeks) is now frequently used
for patients undergoing total hip re-
placement surgery than for patients
undergoing total knee replacement
surgery (30 days). Trials involving
the newer anticoagulants dabigatran
and rivaroxaban have explored pro-
phylaxis of 28–35 days and 35 days,
respectively.17
Knee and hip replacement surger-
ies are invasive, traumatic procedures.
All three components of Virchow’s
triad (endothelial injury, circulatory
stasis, and a hypercoagulable state)
are present and promote thrombus
formation in patients undergoing
these surgeries. The amount of surgi-
cal blood loss has diminished with
newer surgical techniques, and this
may reduce any delay in starting
prophylaxis and the risk for VTE.
Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
Regardless, a high risk for VTE is as-
sociated with lower-extremity ortho-
pedic procedures unless prophylaxis
is provided. In the absence of VTE
prophylaxis after knee replacement
surgery, the risk for proximal DVT
is 5–22% and PE is 1.5–10%.5 After
untreated hip replacement surgery,
the risk for proximal DVT is 18–36%
and the risk for PE is 0.9–28%.5
Fatal PE poses the greatest con-
cern, regardless of the reason for
hospitalization. The incidence in
orthopedic surgery patients appears
to be low when prophylaxis is used
(0.1%), although the true incidence
of fatal PE is unknown because au-
topsies in cases of sudden death often
are not performed. 18 Asymptom-
atic VTE confirmed by venography
is much more common than fatal
PE, even when prophylaxis is used.18
Asymptomatic VTE is a concern be-
cause of the potential for long-term
consequences (e.g., postthrombotic
syndrome characterized by persistent
edema, pain, purpura, dermatitis,
pruritus, cellulitis, and ulceration).19
Warfarin
Determining the appropriate tar-
get range for INR during prophylac-
tic warfarin therapy is a dilemma for
clinicians. The target range recom-
mended by ACCP for VTE treatment
as well as prophylaxis in most situa-
tions is 2.0 to 3.0.5,20 This goal also is
recommended by ACCP during war-
farin therapy in patients with atrial
fibrillation to decrease the risk of
cardioembolic stroke.21 The American
Academy of Orthopaedic Surgeons
(AAOS) recommends a goal INR of
2.0 or less for prevention of PE in
patients undergoing total hip or knee
replacement.8 AAOS recommends
warfarin therapy for two to six weeks
starting the night before, or after, hip
or knee replacement surgery.8 How-
ever, the AAOS recommended range
is not as well supported by evidence
as are the ACCP guidelines.8 The goal
INR range used in most published
studies of patients undergoing hip
S11
4/27/2010 2:57:36 PM
 SYMPOSIUM  Assessing and reducing the risk
or knee replacement is 2.0 to 3.0,
although lower ranges (e.g., 1.8 to
2.5, 1.5 to 3.0) have been studied.22,23
However, the target range of 1.5 to
2.0 has not been adequately studied.
Limited data are available on the goal
INR range in patients undergoing
hip fracture surgery.24
An INR greater than 1.8 with
warfarin therapy might reflect suf-
ficient anticoagulation to prevent or
treat established subclinical throm-
bosis in patients for whom bleeding
concerns are present. A model for
warfarin dosing suggests that a target
INR range of 1.7 to 3.3 might be ac-
ceptable for patients at risk for VTE,
although this model requires valida-
tion.25 However, according to ACCP,
INR values less than the recom-
mended range (2.0 to 3.0) may not
provide adequate protection against
VTE, and such values do not neces-
sarily reduce the risk of bleeding.5
Because of concern about spinal
hematoma formation in patients
with epidural catheters, warfarin
initiation should be delayed for at
least two hours after removal of the
epidural catheter.5 The first INR
measurement should not be taken
for at least 12 hours after warfarin
initiation because of the lag time
before any effect on the INR in more
sensitive patients may occur.26 When
the first dose is given the night before
or after surgery, the goal INR range
usually is not reached until the third
postoperative day or later.5
Several bedside factors should be
taken into consideration in providing
warfarin therapy for VTE prevention.
In the early postoperative period,
fluid may be collected from drains
implanted at the surgical site. The
appearance of substantial amounts
of blood in the drainage container
may be a signal of transient sensitiv-
ity to warfarin or may suggest exces-
sive bleeding and the need to watch
the INR response and warfarin dose
accordingly.
For various reasons (e.g., inter-
ruption of the medication admin-
S12 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
5b-Advantage_10-0177.indd 12
istration process by a diagnostic
procedure), hospitalized patients do
not always receive their medications
at the proper times, although medi-
cation administration and dispens-
ing cabinet records might suggest
otherwise. In evaluating the absence
of an INR response and adjustment
of the warfarin dose, the possibility,
albeit uncommon, that a patient did
not receive or take his or her dose of
warfarin should be considered.
Patient education can play a
critical role in the success of warfarin
therapy after hospital discharge. The
proper timing of this education for
surgical patients is important be-
cause they typically are in pain and
may be unable to retain information
and instructions provided during the
early postoperative period. However,
waiting until hospital discharge to
provide patient education is inadvis-
able because of the high likelihood
that the patient will be overwhelmed
with information about other aspects
of home care. In planning patient
education about warfarin and other
drug therapies that will be used at
home, coordination with other
members of the health care team,
particularly nurses, is wise.
Aspirin
There is a lack of consensus
among orthopedic surgeons, chest
physicians, and other practitioners
on the use of aspirin for VTE pro-
phylaxis. AAOS considers aspirin
alone an option for PE prophylaxis
in patients undergoing total hip or
knee replacement, especially patients
at high risk for bleeding.8 The dosage
recommended by AAOS is 325 mg
twice daily for six weeks starting the
day of surgery, although 81 mg/day
may be used if gastrointestinal symp-
toms develop.8 By contrast, ACCP
recommends against the use of as-
pirin alone as thromboprophylaxis
for any patient group.5 This grade
1A recommendation is a strong one
based on randomized trials with con-
sistent results.27
In the Pulmonary Embolism Pre-
vention (Pep) trial, a large, random-
ized, placebo-controlled study of
patients undergoing hip or knee re-
placement or hip fracture surgery, as-
pirin 160 mg/day for 35 days starting
preoperatively significantly reduced
the incidence of VTE by 36%, from
2.5% with placebo to 1.6% with as-
pirin (p = 0.0003).28 Both treatment
groups received the study drug in
combination with whatever prophy-
laxis was considered necessary. In-
terpretation of the Pep study results
is complicated by the extensive use
of post-hoc analysis. Surprisingly, a
higher incidence of acute myocardial
infarction was observed in the aspi-
rin group than in the placebo group.
Additional data are needed to resolve
the controversy surrounding the use
of aspirin alone for VTE prophylaxis
in orthopedic surgery patients.
LMWH
The use of LMWH products
for VTE prophylaxis is not always
straightforward, especially for pa-
tients with certain unique needs. The
LMWH usually is initiated 12–24
hours after hip or knee replacement
surgery, which is consistent with
recommendations from both ACCP
and AAOS. 5,8 Subsequent dosing
should be provided in accordance
with the manufacturer’s prescribing
information; the dosing interval usu-
ally is every 12–24 hours, although an
interval of 24 hours may be preferred
for long-term prophylaxis.
The effects of enoxaparin are in-
creased in patients with severe renal
impairment (i.e., creatinine clear-
ance <30 mL/min, which includes
chronic kidney disease [CKD] stage
4 or 5), and the risk of bleeding com-
plications may be increased. Most of
the data driving this recommenda-
tion came from patients with CKD
stage 3 or 4, not dialysis-dependent
CKD. Therefore, dosage reduction
(e.g., decreasing the enoxaparin dose
by 50% or increasing the dosing in-
terval from 12 hours to 24 hours) is
4/27/2010 2:57:45 PM

recommended when the creatinine
clearance (CrCl) is between 20 and
30 mL/min.20 Patients on hemodi-
alysis and those with CKD stage 5
were excluded from clinical trials;
therefore, dosing in this population
remains unclear. Tinzaparin and
dalteparin appear safe to use without
dosage adjustment or anti-factor Xa
monitoring in patients with CrCl
that exceeds 20 mL/min.30,31
Although four to six weeks of
VTE prophylaxis appears warranted
after total hip and knee replacement
surgery, the ACCP guidelines recom-
mend VTE prophylaxis with LMWH
for at least 10 days and extended pro-
phylaxis for up to 35 days for patients
undergoing hip or knee replacement
surgery or hip fracture surgery.5,16
The recommended duration of
LMWH in the AAOS guidelines is
7–12 days.8 As part of the preop-
erative evaluation, selection of the
pharmacologic agent to be used after
discharge should take into consider-
ation the costs and available options
on the patient’s insurance plan so
that authorization can be obtained,
if needed.
Dosing of LMWH products in pa-
tients with obesity has been studied
because of concerns about a poten-
tially increased risk for VTE due to
inadequate prophylaxis when fixed
doses of LMWH are used in this pa-
tient population. In a retrospective,
multicenter study, 817 orthopedic
surgery patients received fixed sub-
cutaneous (s.c.) doses of enoxaparin
40 mg/day starting 12 hours before
surgery. 32 The incidence of VTE
detected with bilateral venography
during postoperative days 7–10 was
18.7%. There was no relationship
between body weight or body surface
area and thrombosis, but there was
a strong relationship between body
mass index (BMI) and thrombosis
(p  = 0.0002). The incidence of VTE
was 31.8% in patients with a BMI
exceeding 32 kg/m2 (i.e., obese pa-
tients) and 16.7% in patients with a
BMI less than 32 kg/m2 (p < 0.001).
5b-Advantage_10-0177.indd 13
SYMPOSIUM  Assessing and reducing the risk
There was no relationship between
bleeding and BMI.
Two s.c. enoxaparin dosing regi-
mens were compared in a non-
randomized study of 481 patients
undergoing bariatric surgery for
morbid obesity.33 The first 92 pa-
tients enrolled received 30 mg every
12 hours, and the subsequent 389 pa-
tients received 40 mg every 12 hours.
Early ambulation, GCS, and IPC
were used in both groups. The two
groups had a similar BMI (51.7 kg/
m2 for the first group and 50.3 kg/m2
for the second group). The duration
of the procedure decreased over time
suggeting a potiential bias in favor
of the 40-mg cohort. The incidence
of postoperative DVT complications
was significantly lower (0.6%) in the
second group (the group receiving
the larger enoxaparin dosage) than in
the first group (5.4%, p < 0.01). One
patient in each group required treat-
ment for hemorrhage (i.e., the larger
enoxaparin dose was not associated
with an increased risk for bleeding).
However, duration is another con-
sideration. In a single practitioner’s
report of experience with 308 con-
secutive bariatric surgery patients,
the incidence of thromboembolism
was significantly higher in patients
who received 3 days (4.5%) of pro-
phylaxis than in those who received
10 days (0%) of prophylaxis. The
patients’ mean BMI was 47 kg/mm2,
and the enoxaparin dose was 30
mg twice daily for the duration of
hospitalization (approximately two
to three days) and 40 mg once daily
after discharge.34
A subgroup analysis of the Pro-
spective Evaluation of Dalteparin
Efficacy for Prevention of VTE in
Immobilized Patients (Prevent)
trial, which compared dalteparin
5000 units/day with placebo, dem-
onstrated no difference in outcomes
between obese (BMI 34  ±  5 kg/m2, n
= 1118) and non-obese (BMI 25  ±  4
kg/m2, n = 2563) subjects.35 Additional
information is needed to determine
the possible benefit of dalteparin
Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
doses greater than 5000 units/day in
morbidly obese patients.
In a small analysis of VTE prophy-
laxis with 40 mg of enoxaparin after
total hip arthroplasty or total hip re-
placement, injection into the thigh in
patients with a BMI over 25 kg/mm2
was associated with a loss of anti-Xa
activity, compared with other sites.36
Analysis of the results of these
and other studies has led some clini-
cians to recommend increasing the
dosages of LMWH used for VTE
prophylaxis in patients with morbid
obesity (i.e., a BMI of 40 kg/m2 or
higher) by 30% over dosages used for
nonobese patients.29 Clinical practice
guidelines have yet to include such a
recommendation.
The efficacy of LMWH for VTE
prophylaxis may be diminished in
critically ill patients in the intensive
care unit (ICU) because of anti-
thrombin deficiency, fluid overload,
edema, or other factors.37-39 In 89 ICU
patients, therapeutic anti-factor Xa
levels (0.1–0.3 IU/mL) were achieved
4 hours, 12 hours, and 24 hours after
a 40-mg s.c. dose of enoxaparin in
56.5%, 39.3% and 12.6% of the pa-
tients, respectively.38
The pharmacokinetics and phar-
macodynamics of enoxaparin 30 mg
s.c. every 12 hours were compared in
two cohorts of critically ill patients
suffering from multiple trauma with
or without a 10-kg or greater increase
in body weight due to peripheral ede-
ma.37 The area under the curve (AUC)
for plasma anti-factor Xa activity
over the 12-hour period after a dose
was highly variable in both groups.
The 12-hour AUC, peak plasma anti-
factor Xa activity, and antithrombin
activity were significantly lower in
the patients with edema than in those
without edema (p < 0.05).
Another study compared a group
of 16 ICU patients with a group of
13 noncritically ill medical patients.39
The AUC for anti-factor Xa activ-
ity over the 12-hour period after
a 40-mg s.c. dose of enoxaparin
was significantly lower in the ICU
S13
5/3/2010 2:48:35 PM
 SYMPOSIUM  Assessing and reducing the risk
patients than in the noncritically ill
medical patients (p = 0.008).39
Fondaparinux
The use of fondaparinux for VTE
prophylaxis can be problematic
in certain settings secondary to its
extended duration of activity and
potential for a higher level of anti-
coagulant effect. ACCP recommends
(grade 1A) fondaparinux 2.5 mg s.c.
once daily starting six to eight hours
after or the next day after hip fracture
surgery and other major orthopedic
surgeries.5 The dosing used for VTE
prophylaxis may have a therapeutic
effect on subclinical thrombosis that
develops during surgery. In a meta-
analysis of four studies comparing
the efficacy of fondaparinux 2.5 mg
s.c. once daily with s.c. enoxaparin
30 mg twice daily or 40 mg once
daily for preventing VTE in patients
undergoing major hip or knee sur-
gery, the incidence of VTE confirmed
by venography (i.e., asymptomatic
VTE) was significantly lower with
fondaparinux (6.8%) than with
enoxaparin (13.7%, p < 0.001).18 In
Phase II fondaparinux dose-finding
clinical trials, no significant differ-
ences in outcomes were observed
with daily doses ranging from 2.5
mg to 12 mg in patients with acute
coronary syndrome or 5 mg to 10
mg in patients with established
VTE.40,41 Results in the OASIS 5 trial
showed no difference between 2.5
mg of fondaparinux and 1 mg/kg
twice-daily warfarin.42 In obese and
nonobese patients receiving fonda-
parinux for the treatment of VTE
(i.e., to prevent VTE recurrence),
which involves fixed 10-mg doses for
patients weighing more than 100 kg ,
the incidence of bleeding decreased
as weight increased.43 However the
efficacy of the drug in preventing
VTE recurrence was not diminished
by an increase in weight. These ob-
servations support the theory that
prophylactic dosing of fondaparinux
for prevention of VTE has a potential
therapeutic antithrombotic effect.
S14 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
5b-Advantage_10-0177.indd 14
In August 2009, the Food and
Drug Administration (FDA) issued a
warning not to administer the initial
fondaparinux dose earlier than six to
eight hours after surgery because of
the risk of bleeding.44, 45 Spinal hema-
toma formation is a concern during
the insertion of epidural catheters in
patients receiving fondaparinux (or
other anticoagulants), so the drug
should be discontinued sufficiently
in advance of the placement of an
epidural catheter.5 The anticoagulant
effect of fondaparinux can persist
for two to four days after the drug is
discontinued.46
Heparin-induced
thrombocytopenia
Heparin-induced thrombocy-
topenia (HIT) is a rare immune-
mediated adverse effect associated
with LMWH and UFH therapy that
clinicians need to be aware of be-
cause it increases the risk for throm-
bosis.47 The risk for HIT depends on
the duration of heparin exposure
and the dosage used. The condition
typically develops if heparin therapy
is continued for a week or longer. It
also may develop later if the patient
is re-exposed to heparin within 100
days, especially within one month.
Whether VTE in a patient discharged
from the hospital receiving heparin
for VTE prevention represents HIT
or failure of prophylaxis (e.g., nonad-
herence) can be difficult to ascertain.
In delayed-onset HIT, thrombocy-
topenia may occur up to 40 days
after heparin therapy is discontinued.
Given the potential for VTE to occur
after discharge, the platelet count
should be checked in any patient
with VTE after recent surgery. If
more than 100 days has elapsed since
heparin therapy was administered,
the risk for VTE is similar between
heparin-naïve patients and those
with a history of HIT.
The development of HIT requires
discontinuation of heparin. Fonda-
parinux is one option that has been
used to treat HIT, although rare cases
of HIT-type reactions and throm-
bosis have been reported in patients
receiving fondaparinux.48 The direct
thrombin inhibitors typically are the
initial anticoagulants used in the set-
ting of HIT. One treatment option
that is currently available for prophy-
laxis in patients with a recent history
of HIT might be lepirudin admin-
istered subcutaneously.47 Emerging
anticoagulants that may prove useful
in patients with HIT include the oral
direct factor Xa inhibitor rivaroxa-
ban and desirudin, a direct thrombin
inhibitor given by s.c. injection.49,50
The cost of using these agents is cur-
rently unknown until available.
The reported risk for HIT is high-
est among patients undergoing or-
thopedic, cardiac, and vascular sur-
gery who receive UFH for one to two
weeks.47 When examining a consecu-
tive series of 146 patients with suf-
ficient suspicion of HIT for initiating
a direct thrombin inhibitor at UC
Davis Medical Center, HIT was not
found in any orthopedic patients.51
During this period, none of the more
than 900 orthopedic surgery patients
who received a short course of UFH
while transitioning to warfarin de-
veloped HIT.51 The lack of HIT with
the use of heparin in this population
was attributed to the short-term use
of UFH and transition to warfarin
for a minimum of one month for
prophylaxis.
Surveillance ultrasound
The use of ultrasound screening
for DVT after orthopedic surgery has
been suggested as a way of identify-
ing patients for treatment. The clini-
cal usefulness of such screening was
evaluated in a study of 346 patients
undergoing hip or knee replace-
ment surgery followed by 10 days of
LMWH therapy.52 Patients were ran-
domly assigned to receive prolonged
prophylaxis with LMWH for an ad-
ditional three weeks or postoperative
ultrasound screening for proximal
and distal thrombosis. Therapeutic
anticoagulation was provided to pa-
4/28/2010 2:43:49 PM

tients in whom thrombosis was de-
tected by screening, but patients with
negative screening results did not
receive additional LMWH therapy
after day 10. The incidence of symp-
tomatic VTE 35 days after hip or knee
replacement surgery was 4.3% with
prolonged prophylaxis and 2.3%
with screening, a difference that was
not significant (p = 0.37). Screening
did not reduce the rate of symptom-
atic VTE over the subsequent three-
month follow-up period.
Guidelines from ACCP recom-
mend against the routine use of
ultrasound screening for DVT before
hospital discharge of asymptomatic
patients after major orthopedic sur-
gery (grade 1A) because ultrasound
screening is unreliable.5 Moreover,
positive ultrasound test results could
affect institutional performance
reports on Joint Commission and
National Quality Forum core per-
formance measures and SCIP out-
come measures. Further, they could
reduce reimbursement from CMS
(the agency considers VTE after total
hip or knee replacement surgery an
avoidable “never event”).
Team approach
In providing VTE prophylaxis, the
risk for thrombosis must be weighed
against the risk for bleeding from
prophylactic interventions. The risk
for thrombosis usually is a concern
for internists, whose primary goal is
ensuring that adequate prophylaxis is
given for the proper duration on the
basis of risk factor assessment. The
risk for bleeding usually is a concern
for surgeons primarily in the early
postoperative period, and the timing
of pharmacotherapy to avoid bleed-
ing during this period is a challenge.
Health-system pharmacists should
collaborate with other members of
the health care team in preventing
VTE, especially for patients with
unique needs (e.g., patients with se-
vere renal impairment, morbid obe-
sity, epidural catheters, or HIT and
critically ill patients). Managing lab-
5b-Advantage_10-0177.indd 15
SYMPOSIUM  Assessing and reducing the risk
oratory values alone has limitations
and is insufficient; input is needed
from clinicians who can make pa-
tient assessments at the bedside.
Conclusion
Clinicians face a variety of chal-
lenges in identifying patients at risk
for VTE and devising prophylactic
strategies. Patients at risk for VTE are
a heterogenous group with diverse
characteristics and needs, and many
questions remain about the optimal
pharmacotherapeutic approach to
meet their needs. Health-system
pharmacists can improve outcomes
in patients at risk for VTE by gain-
ing an understanding of the issues
involved in patient assessment and
prophylactic drug therapy and by us-
ing evidence-based clinical practice
guidelines and their clinical expertise
to advise other members of the care
team about the proper use of drug
therapies for VTE prophylaxis.
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controlled trial. Thromb Haemost. 2003;
90:949-54.
4/27/2010 2:58:20 PM
 SYMPOSIUM  Emerging anticoagulants

Emerging anticoagulants for venous

thromboembolism prevention
Toby C. Trujillo

V
enous thromboembolism (VTE),
especially as a hospital-acquired
condition, should be of concern
to all health care practitioners. VTE
incurs significant morbidity and
mortality for individual patients, as
well as significant overall costs to the
health care system. In addition,
pulmonary embolism (PE) is the
number one preventable cause of
death for hospitalized patients. As
we consider how to meet quality
measures for the prevention and
treatment of VTE, we need to be
cognizant of advances in VTE
prevention strategies that may
help overcome shortcomings of
the currently available pharmaco-
logic and mechanical options for
prophylaxis.
It is of course appropriate for
pharmacists to focus on advances in
anticoagulant therapy, but it is also
important to be aware of changes
in medical practice that may affect
the overall risk of VTE. For example,
operative techniques for orthopedic
procedures have changed substan-
tially, and the changes most likely
Purpose. To discuss the advantages and
disadvantages of currently available an-
ticoagulants, describe the characteristics
of the ideal anticoagulant, and compare
and contrast the mechanisms of action,
pharmacokinetics, administration, efficacy,
safety, and potential for drug interactions
of currently available and emerging antico-
agulants for prevention of venous throm-
boembolism (VTE).
Summary. Despite the proven efficacy of
currently available agents for VTE preven-
tion, several shortcomings exist that may
prevent their use under various circum-
stances. These include administration by
injection, narrow therapeutic index, unpre-
dictable pharmacokinetics and pharmaco-
dynamics, need for laboratory monitoring,
risk for bleeding, and drug interactions.
The ideal anticoagulant would overcome
many of these issues; in particular, it would
be available as an oral formulation. Dab-
igatran, an oral direct thrombin (factor IIa)
inhibitor, and apixaban and rivaroxaban,
oral direct factor Xa inhibitors, represent
affect overall VTE risk. Another
example is the lower overall risk of
VTE with epidural anesthesia versus
general anesthesia.1 These factors
new agents for anticoagulation that may
address many of these issues. While not
available as an oral agent, desirudin is an
additional option and offers increased flexi-
bility when a non-heparin-based injectable
anticoagulant is desired. Current literature
indicates that these agents generally do
not require laboratory monitoring and
are safe and effective for VTE prevention
in clinical studies of patients undergoing
major orthopedic surgery.
Conclusion. The development of new anti-
coagulants that may overcome limitations
of existing agents represents an opportunity
to further improve outcomes in patients at
risk for VTE in orthopedic surgery.
Index terms: Anticoagulants; Apixaban;
Dabigatran; Desirudin; Dosage; Drug
administration; Drug interactions; Hem-
orrhage; Mechanism of action; Pharma-
cokinetics; Rivaroxaban; Surgery; Toxicity;
Venous thromboembolism
Am J Health-Syst Pharm. 2010; 67(Suppl
6):S17-25
typically enter into the operating
physician’s choice of VTE preven-
tion strategy. Much has been made
in the literature of differences be-

Toby C. Trujillo, Pharm.D., BCPS (AQ Cardiology), is ­Associate
Professor, School of Pharmacy, University of Colorado Denver, and
Clinical Specialist—Cardiology/Anticoagulation, University of Colo-
rado Hospital, Aurora, Colorado.
Address correspondence to Dr. Trujillo at 1904 Breen Lane, Supe-
rior, CO 80027 (tobytrujillo12@gmail.com).
Based on the proceedings of a symposium held December 8,
2009, during the 44th ASHP Midyear Clinical Meeting and Exhibi-
tion in Las Vegas, Nevada, and supported by an educational grant
from ­Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharma-
ceuticals, Inc., administered by Ortho-McNeil Janssen Scientific
Affairs, LLC. Dr. Trujillo reports that he has served as a consultant
for Ortho-McNeil.
Dr. Trujillo received an honorarium from the American Society of
Health-System Pharmacists for his participation in the symposium
and for his work on this article. This article was developed with the
assistance of a medical writer working with ASHP Advantage. The
medical writer, Susan R. Dombrowki, M.S., reports that the she has no
relevant financial relationship with a commercial interest, as defined
by the Accreditation Council for Pharmacy Education. The author ap-
proved the final article and all its content.
Copyright © 2010, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/10/0502-0S17$06.00.
DOI 10.2146/ajhp100178

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 SYMPOSIUM  Emerging anticoagulants
tween the American Academy of
Orthopaedic Surgeons 2 (AAOS)
and American College of Chest
Physicians 3 (ACCP) recommen-
dations for prevention of throm-
boembolic disorders in major
orthopedic procedures. Although
it is appropriate to question the
methodological soundness of the
AAOS guidelines, it is also appro-
priate to recognize the importance
of incorporating the perspective of
the operating physician into deci-
sions about VTE prevention for
individual patients and the devel-
opment of a standard approach at a
health care institution. Orthopedic
surgeons are now focusing more on
VTE prevention than they have in
the past, in part because of the need
for accountability to accreditation
and governmental groups for VTE
as an outcome in their patients.
New anticoagulant options for VTE
prevention will need to take into
consideration the priorities of all
parties caring for patients at risk
for VTE.
Figure 1. Current anticoagulant options. Adapted from Kubitza D, Becka M, Voith B et
al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an
oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005; 78:412–21 and Weitz JI, Bates
SM. New anticoagulants. J Thromb Haemost. 2005; 3:1843–53.
S18 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
5b-Advantage_10-0178.indd 18
Evolution of anticoagulants
Many advances have been made
in anticoagulant therapy since the
1930s and 1940s when unfractionated
heparin (UFH) and the vitamin K
antagonist warfarin were the primary
options for treating patients.4 Most of
these advances have resulted from ef-
forts to overcome the shortcomings of
UFH and warfarin and focus on more
specific targets in the coagulation
cascade to improve safety, efficacy,
and convenience. The shortcomings
of these older agents include a nar-
row therapeutic index, unpredictable
pharmacokinetics and pharmacody-
namics (i.e., dose-response relation-
ship), need for laboratory monitoring,
and risk for bleeding. Warfarin, which
is administered orally, provides some
advantages over injectable antico-
agulants. However, warfarin exhibits
complex pharmacokinetics and phar-
macodynamics and interacts with
many medications and foods. These
issues, along with patient nonadher-
ence, make the drug less than ideal in
many circumstances.
Low molecular weight heparin
(LMWH) products were introduced
in the 1980s, and direct thrombin
inhibitors (DTIs; e.g., argatroban,
lepirudin, bivalirudin) and the pen-
tasaccharide fondaparinux became
available in the 1990s. These drugs
overcame many of the disadvantages
of UFH and may be the preferred
agents in many clinical circum-
stances. However, they still require
intravenous (i.v.) or subcutaneous
(s.c.) administration, are more costly
than UFH, and, depending on the
specific agent, may be contraindicated
or difficult to use in patients with
hepatic or renal dysfunction. New
anticoagulants under development
may provide advantages over the cur-
rent injectable agents and warfarin.
Desirudin, an injectable DTI, has
been approved for VTE prevention in
orthopedic surgery since 2003. Com-
pared with other DTIs, desirudin will
likely be available in a dosage form
that is more amenable with VTE
prevention. New oral agents have
the potential to be used in a variety
of settings and may eventually take
the place of warfarin in prophylactic
and therapeutic regimens for many
patients.
Despite advances over the years,
most currently available anticoagu-
lants affect multiple components of
the coagulation cascade (Figure 1).
UFH, LMWHs, and fondaparinux all
inhibit coagulation proteins by bind-
ing to antithrombin and accelerat-
ing its ability to inactivate clotting
factors. The clotting factors affected
include factor Xa and factor IIa
(thrombin), although the extent of
inhibition of each varies depending
on the agent being used.5,6 Warfarin
and other vitamin K antagonists
also affect multiple coagulation
proteins and disrupt the production
of functional vitamin K-dependent
clotting factors II, VII, IX, and X as
well as the anticoagulant proteins C
and S.7 Argatroban, lepirudin, and
bivalirudin are DTIs that do not bind
antithrombin.6 The development of
4/27/2010 2:59:11 PM
 SYMPOSIUM  Emerging anticoagulants

new agents has led to the identifica- A new oral vitamin K antagonist, for dabigatran was not submitted to
tion of compounds that directly tar- tecarfarin, is currently in develop- FDA in 2009 as had been expected.
get and inhibit specific coagulation ment.16 Tecarfarin is not metabolized An FDA advisory committee recom-
proteins. by cytochrome P-450 enzymes, so its mended approval of rivaroxaban
The currently available antico- use circumvents many of the con- in March 2009.20 However, in May
agulants have many limitations. cerns about drug interactions associ- 2009 additional information was
The need for s.c. administration ated with warfarin. A recent study requested by FDA, although no new
of LMWH and fondaparinux and demonstrated that a higher level of clinical or nonclinical studies were
i.v. administration of DTIs is a international normalized ratio (INR) requested.21
disadvantage for patients requiring control may be achievable with tecar- Pharmacokinetic and pharmaco-
extended VTE prophylaxis in the farin than with warfarin in patients dynamic characteristics of emerging
outpatient setting (e.g., patients with atrial fibrillation. anticoagulants are listed in Table 1.
recovering from hip replacement The agents that have received the Desirudin has a short half-life of only
surgery). The need for enoxaparin most attention recently and are the 2 hours, similar to other commer-
dosing adjustment in patients with most likely to come to market in the cially available DTIs. Although de-
severe renal impairment (creatinine near future include the oral direct sirudin is eliminated primarily by the
clearance <30 mL/min), the lack of thrombin (factor IIa) inhibitor dab- kidney, its short half-life and ability
data for dosing dalteparin in pa- igatran and two oral direct factor Xa to be monitored by activated partial
tients with severe renal impairment, inhibitors, apixaban and rivaroxaban thromboplastin time (aPTT) make
and the risk of heparin-induced (Table 1).17-19 Dabigatran and rivar- it a potential option for patients who
thrombocytopenia can limit the use oxaban have been available in Europe have various levels of renal insuffi-
of LMWH.8,9 Fondaparinux is con- and Canada since 2008 for use in the ciency. The current labeling provides
traindicated in patients with severe prevention of deep vein thrombosis specific dosing recommendations for
renal impairment.10 The available (DVT) and PE in major orthopedic various levels of renal function. In
DTIs should be used cautiously in procedures. Rivaroxaban is the only addition, routine aPTT monitoring
patients with organ dysfunction agent among the three for which would allow patients who are ac-
(renal impairment for lepirudin a new drug application has been cumulating unsafe drug levels to be
and bivalirudin, and hepatic im- submitted to FDA. An application identified and dosing to be adjusted.
pairment for argatroban), and data
on their use in VTE prevention are
limited.11-13
Figure 2. Targets for new anticoagulants. Adapted from reference 14.
Emerging anticoagulants
A large number of oral and inject-
able anticoagulants that target factor
Xa, factor IIa, or other components
of the coagulation cascade are in
development and have potential
applications in VTE prevention,
treatment, or both (Figure 2).14,15
Desirudin is an injectable DTI typi-
cally administered via the s.c. route.
The drug was approved by the Food
and Drug Administration (FDA) in
2003 for prevention of VTE in major
orthopedic procedures and became
commercially available in 2010. De-
sirudin provides an option when an
injectable DTI is preferable for the
prevention and possibly treatment of
thromboembolic diseases.
Altering the molecular structure
of warfarin to address some of its
shortcomings has been investigated.

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 SYMPOSIUM  Emerging anticoagulants

This agent would be an option for
patients requiring non-heparin an-
ticoagulant therapies, as an alterna-
tive to the synthetic pentasaccharide
fondaparinux.
The times to peak plasma con-
centration and half-lives of the three
emerging oral anticoagulants dab-
igatran, rivaroxaban, and apixaban
are similar. Their half-lives facilitate
administration once or twice daily.
The bioavailability of dabigatran is
low, requiring the administration of
large doses to achieve therapeutic
concentrations. In addition, dab-
igatran is administered as a prodrug,
dabigatran etexilate, that requires an
acidic environment for absorption.18
Therefore, clinically relevant interac-
tions with proton pump inhibitors
and other acid-suppressing therapies
are likely for dabigatran.19 However,
the risk for drug interactions with
dabigatran is low compared with
the other emerging agents because
cytochrome P-450 enzymes are not
involved in metabolism of the drug.22
Since dabigatran is eliminated pri-
marily by the kidneys, dosage reduc-
tion may be required for patients
with renal impairment.22 Drug accu-
mulation is a concern because of the
potential for bleeding, and further
research is needed to fully character-
ize how the drug may be used safely
in patients with various levels of re-
nal impairment.
In contrast to dabigatran, the
bioavailability of apixaban and ri-
varoxaban is greater than 50% and
80%, respectively.17,18,23 Renal elimi-
nation is higher for rivaroxaban
(66%) than for apixaban (25%), but
the 66% for rivaroxaban includes an
inactive metabolite. Approximately
30% of the parent drug is cleared
by the kidneys in patients taking
rivaroxaban. 6 Nevertheless, renal
impairment may be a consideration
in the dosing of rivaroxaban. Apixa-
ban is less likely than rivaroxaban
to accumulate in patients with renal
impairment. Although use in pa-
tients with renal impairment may
be of less concern with apixaban
and rivaroxaban, both agents are
metabolized by cytochrome P-450
3A4.18 These drugs can interact with
potent inhibitors of both CYP3A4
and P-glycoprotein, and their use
will likely require a level of vigilance
for potential drug interactions simi-
lar to that for warfarin.
Dabigatran efficacy and safety.
The efficacy and safety of dabigatran
for VTE prevention was explored
in three key clinical trials involving
patients undergoing major orthope-
dic surgery.24-26 Dabigatran was com-
pared with s.c. enoxaparin in three
randomized double-blind studies,
two of which looked at VTE preven-
tion in patients undergoing total
knee replacement surgery (known as
RE-MOBILIZE and RE-MODEL),
while the third study, known as
RE-NOVATE, was conducted in pa-
tients undergoing total hip replace-
ment surgery (Table 2).24-26 The same
primary efficacy outcome (total VTE
events and all-cause mortality) was
used in all three studies, but the bleed-
ing definitions used in the safety anal-
ysis varied somewhat. The same two
dabigatran dosages (150 mg or 220
mg twice daily) were used in all three
studies, although a half dose was used
as the initial dose in RE-NOVATE.
The timing of the first dose was 1-4
hours after surgery in two studies
(RE-MODEL and RE-NOVATE)
and 6-12 hours after surgery in the
other study. The duration of therapy
was shorter in the RE-MODEL and
RE-MOBILIZE studies of knee
replacement patients than in
RE-NOVATE (i.e., hip replacement
patients), but this difference is
appropriate given the current
guideline-based recommendations
for duration of VTE prophylaxis
in these two patient populations.14

Table 1.
Characteristics of Emerging Anticoagulants6,17-19

Characteristic Dabigatran Etexilatea Apixaban Rivaroxaban Desirudin

Mechanism of action Thrombin (factor IIa) Factor Xa inhibition Factor Xa inhibition Thrombin (factor IIa)
  inhibition inhibition
Time to peak plasma 2-3 3 3 1-3
concentration (hr)
Bioavailability (%) 6 >50 80 N/A
Half-life (hr) 12–17 9–14 5–9 2
Dosing frequency Once or twice daily Twice daily Once daily Twice daily
Renal elimination (%) 80 25 66b 100 (40-50 parent drug)
Drug interactions Proton pump inhibitors Potent inhibitors Potent inhibitors of Pharmacodynamic with
  of both CYP3A4   both CYP3A4 and   other agents that
  and P-glycoprotein   P-glycoprotein   affect platelet function
  or coagulation
Dabigatran is administered as a prodrug, dabigatran etexilate.
a

Renal elimination of rivaroxaban and its inactive metabolite is 66%. Approximately 30% of the parent drug is cleared by the kidneys.
b

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 SYMPOSIUM  Emerging anticoagulants

The enoxaparin dosing regimen
commonly used in North America
(30 mg twice daily) was used in RE-
MOBILIZE, but the less intense
regimen preferred in Europe (40
mg once daily) was used in the
other two studies. These differences
in dosing are important to consider
because they may have affected the
study results and may have different
implications for clinical practice in
different regions of the world.
In RE-NOVATE (i.e., total hip
replacement surgery patients receiv-
ing the European enoxaparin dosing
regimen), the primary efficacy out-
come (i.e., composite of total VTE
events and all cause mortality) had
occurred after 28–35 days in 53
(6.0%) of 880 patients in the dabiga-
tran 220 mg/day group, 75 (8.6%) of
874 patients in the dabigatran 150
mg/day group, and 60 (6.7%) of 897
patients in the enoxaparin group.
Both dabigatran doses were judged
non-inferior to enoxaparin.26 There
were no significant differences in
the incidence of major bleeding be-
tween enoxaparin (1.6%) and either
dose of dabigatran (2.0%, p = 0.44
for 220 mg/day; 1.3% p = 0.60 for
150 mg/day). Similarly, the rates of
clinically relevant non-major and
minor bleeding did not differ be-
tween enoxaparin and either dose of
dabigatran.
Despite these positive results in
evaluating the potential benefit of
dabigatran in VTE prevention, it is
most instructive to look at the two
studies involving knee replacement
patients (Table 2). In RE-MODEL,
both the 150 mg and 220 mg once
daily dose of dabigitran met the non-
inferiority criteria with enoxaparin
40 mg once daily. In RE-MOBILIZE
(i.e., total knee replacement surgery
patients receiving the North Ameri-
can enoxaparin dosing regimen),
dabigatran was judged inferior to
enoxaparin (i.e., non-inferiority cri-
teria were not met).24 The incidence
of the primary outcome after 12–15
days of treatment was 31% with dab-
igatran 220 mg/day (p = 0.02 versus
enoxaparin), 34% with dabigatran
110 mg/day (p < 0.001 versus enox-
aparin), and 25% with enoxaparin.
Potential explanations for the lack
of positive findings for dabigatran
include the use of a more intense
enoxaparin dosing regimen com-
pared with that used in RE-NOVATE
as well as a lower initial dose of dab-
igatran. The rates of major bleeding
and clinically relevant non-major
bleeding were similar with both dab-
igatran doses and enoxaparin (rates
of minor bleeding were not report-
ed). Thus, on the basis of the current
results, dabigatran appears to be a
potentially useful option for VTE
prevention but may be less effective
than more aggressive regimens of the
LMWH enoxaparin.
Despite the varied results in VTE
prevention, the dabigatran clinical
trial program is a promising one and
includes other studies of the drug for
use in VTE treatment, for thrombo-
sis prevention in patients with atrial
fibrillation, and in conjunction with
antiplatelet therapy for the treatment
acute coronary syndrome (ACS).27,28
In patients with atrial fibrillation,
dabigatran 150 mg twice daily was
associated with lower rates of stroke
and systemic embolism and similar
rates of major hemorrhage com-
pared with warfarin.28 In addition, in
patients with acute VTE, dabigatran
150 mg twice daily was as effective
as warfarin in preventing VTE recur-
rence, with a similar incidence of
bleeding.27
Apixaban efficacy and safety.
The efficacy and safety of apixaban
2.5 mg twice daily and enoxaparin
for VTE prevention in patients un-
dergoing major orthopedic surgery
were compared in three random-
ized, double-blind studies known as

Table 2.
Key Randomized, Double-Blind Clinical Studies Comparing Dabigatran with Enoxaparin for VTE
Prevention in Major Orthopedic Surgery24-26,a,b

Variable RE-MOBILIZE RE-MODEL RE-NOVATE

No. patients 1896 2076 3494
Type of surgery Total knee replacement Total knee replacement Total hip replacement
Dabigatran dosage 150 mg or 220 mg once daily 150 mg or 220 mg once daily 150 mg or 220 mg once dailyb
Timing of initial dabigatran dose 6–12 hr after surgery 1–4 hr after surgery 1–4 hr after surgery
Enoxaparin dosage 30 mg twice daily 40 mg once daily 40 mg once daily
Timing of initial enoxaparin dose 12–24 hr after surgery Evening before surgery Evening before surgery
Treatment duration (days) 12–15 6–10 28–35
Primary endpoint Total VTE and all-cause Total VTE and all-cause Total VTE and all-cause
  mortality   mortality   mortality
Non-inferiority margin (%) 9.2 9.2 7.7
a
All dabigatran doses were administered orally as dabigatran etexilate. All enoxaparin doses were administered subcutaneously.
b
VTE = venous thromboembolism.
c
In RE-NOVATE, the first dabigatran dose was a half dose.

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 SYMPOSIUM  Emerging anticoagulants
ADVANCE-1, 2, and 3. 29,30 Re-
sults have been reported only for
ADVANCE-1 and ADVANCE-2.
Similar to dabigatran, the apixaban
clinical trial program also includes
studies of use of the drug for VTE
treatment, stroke prevention in
patients with atrial fibrillation, and
treatment of ACS in conjunction
with antiplatelet therapy.
ADVANCE-1 involved 3195 pa-
tients undergoing total knee replace-
ment and compared apixaban with
enoxaparin 30 mg s.c. twice daily
beginning 12–24 hours after surgery
and continued for 10–14 days.29 The
primary efficacy outcome was total
VTE events, and the criteria for non-
inferiority included an upper limit
of the 95% confidence interval of
1.25). After 10–14 days of treatment,
the primary efficacy outcome oc-
curred in 9.0% of apixaban-treated
patients and 8.8% of enoxaparin-
treated patients (p = 0.06, relative
risk, 1.02; 95% confidence interval,
0.78 to 1.32). Since the upper bound-
ary of the 95% confidence interval
exceeded 1.25, apixaban did not
meet the criteria for non-inferiority
to enoxaparin. Although the trial
did enroll a sufficient number of
patients based on the prespecified
power analysis, the overall event rate
was much lower than anticipated and
likely influenced the statistical analy-
sis. The incidence of major bleeding
and clinically relevant non-major
bleeding was significantly lower with
apixaban (2.9%) than with enox-
aparin (4.3%, p = 0.03).
ADVANCE-2 involved 3057 pa-
tients undergoing total knee replace-
ment, and the comparison was made
between apixaban and enoxaparin 40
mg s.c. once daily beginning 12 hours
before surgery.30 After 12 days, the
incidence of total VTE events was
significantly lower with apixaban
(15.1%) than enoxaparin (24.4%,
p < 0.001). There was no significant
difference between apixaban and
enoxaparin in the incidence of major
bleeding and clinically relevant non-
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5b-Advantage_10-0178.indd 22
major bleeding (3.5% versus 4.8%,
respectively, p = 0.09).
As with dabigatran, the results of
apixaban clinical trials in patients
undergoing major orthopedic sur-
gery depended on the enoxaparin
dosing regimen used. Although
underlying issues with statistical
power and methodology were likely
in play, the results were less favorable
with the more aggressive regimen of
enoxaparin 30 mg twice daily than
with the 40 mg once-daily regimen.
Additional studies comparing the
efficacy of apixaban with the North
American enoxaparin regimen are
needed.
Rivaroxaban efficacy and safety.
The efficacy and safety of rivaroxa-
ban for preventing VTE in patients
undergoing major orthopedic sur-
gery have been evaluated in four
randomized, double-blind clinical
trials.31-34 The rivaroxaban clinical
trial program also includes studies
of the drug for VTE treatment, VTE
prevention in medically ill patients,
thrombosis prevention in patients
with atrial fibrillation, and treat-
ment of ACS in conjunction with
antiplatelet therapy. Results of the
Einstein-Extension Study of ex-
tended rivaroxaban therapy for 6–12
months in patients with established
VTE were recently reported.35 The
drug was effective for preventing
VTE recurrence, with a low risk for
major bleeding.
Two of the rivaroxaban studies
in patients undergoing major or-
thopedic surgery involved total hip
replacement surgery, and the other
two studies involved knee replace-
ment surgery (Table 3).31-34 The same
rivaroxaban dosage (10 mg once
daily) and primary endpoint (total
VTE or death) were used in all four
studies, but the duration of therapy
and enoxaparin dosage varied. In
the studies of total hip replace-
ment (known as RECORD 1 and
RECORD 2), the European enox-
aparin dosing regimen was used,
but a longer and more appropriate
duration of enoxaparin therapy
was used in RECORD 1 (35 days)
than in RECORD 2 (14 days).31,32
Rivaroxaban was judged superior to
enoxaparin in RECORD 1 because
the incidence of the primary out-
come after 35 days of treatment was
significantly lower in the rivaroxaban
group (1.1%) than in the enoxaparin
group (3.7%, p < 0.001).31 There was
no significant difference between
rivaroxaban and enoxaparin in the
incidence of major bleeding (0.3%
versus 0.1%, respectively, p = 0.18).
The results of RECORD 2 are consis-
tent with these findings.
Rivaroxaban was judged superior
to enoxaparin in the two clinical
studies of patients undergoing knee
replacement surgery.33,34 The results
of RECORD 4 provide greater in-
sight for American clinicians than
the results of RECORD 3 because the
North American enoxaparin dos-
ing regimen was used in RECORD
4 and the European enoxaparin
regimen was used in RECORD 3.
In RECORD 4, the primary efficacy
outcome occurred in significantly
fewer rivaroxaban-treated patients
(6.9%) than enoxaparin-treated
patients (10.1%, p = 0.0118) after
14 days of treatment.34 There was
no significant difference between
rivaroxaban and enoxaparin in the
incidence of major bleeding (0.7%
versus 0.3%, respectively, p = 0.1096).
Similarly, no significant difference
between treatments in major bleed-
ing rates was observed in RECORD
3 (p = 0.93).
Desirudin efficacy and safety.
The efficacy and safety of desiru-
din for preventing VTE in patients
undergoing hip replacement surgery
has been established for over a de-
cade. Two randomized, multicenter,
placebo-controlled trials compared
desirudin at a dose of 15 mg s.c. twice
daily with either UFH 5000 units
three times daily 36 or enoxaparin
40 mg s.c. once daily.37 In the lat-
ter, desirudin was given 30 minutes
prior to surgery after the induction
4/27/2010 2:59:50 PM
 SYMPOSIUM  Emerging anticoagulants

of regional anesthesia if used, while
enoxaparin was initiated the evening
before surgery. Both regimens were
continued for 8–12 days (mean,
9.7 days). The primary endpoint of
major thromboembolic events in-
cluded proximal DVT, fatal or non-
fatal PE, or unexplained death. Of
the 2079 total patients enrolled, 1587
were included in the final analysis,
which showed desirudin to be su-
perior to enoxaparin at preventing
the primary endpoint (4.5% versus
7.5%, p = 0.01). There were no dif-
ferences between the two groups
with respect to rates of blood loss,
serious bleeding, wound hematoma,
or infection.
The ideal anticoagulant
Given the recent focus on new
anticoagulant agents for VTE pre-
vention and for other patient popu-
lations, it is useful to consider what
characteristics an ideal anticoagulant
might have and then to evaluate these
new options against the ideal agent.
The ideal anticoagulant for VTE
prevention would have a wide thera-
peutic index and predictable phar-
macokinetics (i.e., little variability
among patients and within an indi-
vidual) and pharmacodynamics (i.e.,
dose-response relationship), with no
need for laboratory monitoring.23
The drug should be available for both
i.v. and oral administration and have
a rapid onset of action, even after
oral administration. The ideal agent
would be able to be initiated in the
hospital and continued on an outpa-
tient basis to circumvent the bridge
therapy that is sometimes needed
in the transition from injectable
anticoagulants to warfarin for VTE
prevention. Action that is rapidly re-
versible with or without an antidote
is desired. The ideal anticoagulant
would be safe, even when used on a
long-term basis. It should not have
clinically important adverse effects or
interact with common foods or other
drugs. An agent that does not accu-
mulate or require dosage adjustment
in patients with renal or hepatic im-
pairment is preferred. A reasonable
cost also is desired.
While desirudin does not fit many
of these criteria, it does represent an
important addition to the available
options for VTE prevention. It offers
an additional option for patients in
need of a non-heparin based regi-
men. Its short half-life and monitor-
ing by aPTT make it an attractive
option for acutely ill patients. Ac-
cording to the current prescribing in-
formation, with desirudin the aPTT
should not exceed two times the
control value. Dosing recommenda-
tions for patients with various levels
of renal insufficiency are available. In
patients with a creatinine clearance
of 30-60 mL/min, the recommended
dose is 5 mg s.c. every 12 hours. In
patients with a creatinine clearance
of <30 mL/min, the recommended
dose is 1.7 mg s.c. every 12 hours. In
each instance, the aPTT can be used
to monitor for drug accumulation
and excessive anticoagulant effect.
Issues that require further investiga-
tion include use of the agent in knee
replacement patients, its appropriate
use during epidural anesthesia, and
the optimal duration of therapy. In
the clinical trials discussed here, de-
sirudin was given for an average of
10 days. However, current guidelines
recommend 28–35 days of therapy as
the standard of care in hip replace-
ment patients. Additional studies are
needed to characterize the feasibility

Table 3.
Key Randomized, Double-Blind Clinical Studies Comparing Rivaroxaban with Enoxaparin for VTE
Prevention in Major Orthopedic Surgery31-34,a,b

Variable RECORD 1 RECORD 2 RECORD 3 RECORD 4

No. patients 4541 2509 2531 3148
Type of surgery Total hip replacement Total hip replacement Total knee replacement Total knee replacement
Rivaroxaban dosage 10 mg once daily 10 mg once daily 10 mg once daily 10 mg once daily
Timing of initial 6–8 hr after surgery 6–8 hr after surgery 6–8 hr after surgery 6–8 hr after surgery
rivaroxaban dose
Duration of rivaroxaban 35 35 14 14
therapy (days)
Enoxaparin dosage 40 mg once daily 40 mg once daily 40 mg once daily 30 mg twice daily
Timing of initial 12 hr before surgery 12 hr before surgery 12 hr before surgery 12–24 hr after surgery
enoxaparin dose
Duration of enoxaparin 35 14 14 14
therapy (days)
Primary endpoint Total VTE or death Total VTE or death Total VTE or death Total VTE or death
Non-inferiority margin (%) 3.5 N/A 1.5 4
All rivaroxaban doses were administered orally. All enoxaparin doses were administered subcutaneously.
a

N/A = not applicable; NR = not reported; VTE = venous thromboembolism.

b

Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6 S23

5b-Advantage_10-0178.indd 23 4/27/2010 3:00:00 PM

 SYMPOSIUM  Emerging anticoagulants
and cost-effectiveness of desirudin
for the recommended duration of
therapy.38
The emerging oral anticoagu-
lants dabigatran, apixaban, and
rivaroxaban have many but not all
of the characteristics of the ideal
anticoagulant. They offer the op-
tion of oral administration and
elicit a consistent dose response, in
contrast to warfarin. They appear
safe and effective for VTE preven-
tion in patients undergoing major
orthopedic surgery, although data
from additional comparative stud-
ies using the twice-daily enoxaparin
regimen for a sufficient duration are
needed, especially for apixaban and
dabigatran. Laboratory monitoring
is likely not required during therapy
with these drugs, provided that they
are used in a manner consistent with
available clinical trials. However,
many patients will likely fall outside
the strict inclusion and exclusion
criteria of clinical trials, and the
potential to monitor anticoagulant
response will be of high value. Both
dabigatran and rivaroxaban can be
assessed with common tests such
as the aPTT and the prothrombin
time/INR.39,40 However, the correla-
tion between prolongation of these
coagulation assay results and the ef-
ficacy and safety of these agents is as
yet unclear, and more work will be
required before these agents can be
monitored with existing coagulation
tests. Drug interactions mediated by
cytochrome P-450 enzymes are not
an issue with dabigatran, but renal
impairment is of concern. Patients
with significant renal insufficiency
were excluded from clinical studies,
and the drug will likely need to be
avoided in this patient population.
In addition, although baseline renal
function may be sufficient to war-
rant use of dabigatran in a given pa-
tient, rapid changes and fluctuations
in renal function for any reason will
place the patient at risk for drug
accumulation and toxicity. Drug
interactions are among the major
S24 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
5b-Advantage_10-0178.indd 24
challenges with warfarin adminis-
tration. Although the potential for
drug interactions is of less concern
with apixaban and rivaroxaban, it
is by no means nonexistent. Both
agents are metabolized through
cytochrome P450 3A4, and routine
monitoring for potential drug in-
teractions will be needed to ensure
that these agents are used safely and
effectively.
The actions of dabigatran, apixa-
ban, and rivaroxaban are not readily
reversible. The drugs are not likely
to be removed by dialysis, their half-
lives are not short, and no antidotes
are available; therefore, these drugs
are not likely to be options in patients
in whom reversibility is paramount.18
The management of bleeding in
patients receiving these drugs may
be a problem and requires further
investigation.
The costs of dabigatran, apixaban,
desirudin, and rivaroxaban remain to
be determined. However, any analysis
of cost should include the potential
cost savings associated with avoiding
the need for laboratory monitoring
and reducing readmissions for post-
operative VTE. These considerations,
as well as any changes in costs associ-
ated with adverse effects, should be
taken into consideration along with
drug acquisition cost in evaluating
the cost of using these drugs for VTE
prevention.
Conclusion
Several new options for the
pharmacologic prevention of VTE
in major orthopedic surgery have
recently become available or soon
will be available. The new antico-
agulants have many of the charac-
teristics of the ideal anticoagulant,
although significant safety and
efficacy considerations will need to
be addressed for each agent. These
agents have the potential to over-
come many of the shortcomings of
currently available anticoagulants
and to improve outcomes in pa-
tients at risk for VTE.
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S25
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 SYMPOSIUM  Clinical and management challenges

Clinical and management challenges

in preventing venous thromboembolism in health
systems: A case-based panel discussion
Stuart T. Haines, William E. Dager, and Toby C. Trujillo

C
linicians and managers at health
systems face many challenges
in preventing venous throm-
boembolism (VTE) in their institu-
tions. Overcoming these challenges
and improving outcomes requires
an understanding of clinical and
management issues related to VTE
prevention.
Clinical challenge 1
Dr. Haines: Mr. Vegas, a 48-year-
old man who weighs 430 lb (195 kg)
and is 6 feet tall, is admitted to the
hospital for bariatric surgery. He has
a history of deep vein thrombosis
(DVT) in 2006, at which time he was
treated successfully with warfarin for
three months.
Mr. Vegas is at high risk for VTE
after bariatric surgery because of his
history of DVT and obesity.1 The
American College of Chest Physicians
Purpose. To illustrate clinical and manage-
ment issues in the prevention of venous
thromboembolism (VTE) in health systems.
Summary. Lack of evidence to guide the
choice among available anticoagulants
and the dosing, timing of initiation, and
duration of therapy for VTE prevention in
certain clinical situations can present chal-
lenges for clinicians. Patient characteristics
such as the presence of obesity, epidu-
ral catheters, renal impairment, or heparin-
induced thrombocytopenia complicate the
decision-making process. The introduction
of new anticoagulants may overcome some
of the clinical challenges associated with
VTE prophylaxis, but determining whether
to add new agents to the formulary and
(ACCP) guidelines recommend rou-
tine thromboprophylaxis with low
molecular weight heparin (LMWH),
low-dose unfractionated heparin
(UFH) three times daily, fonda-
restrict their use may pose management
challenges. The safety, effectiveness, ease
of use, and cost of new agents compared
with older agents already on the formulary
are primary considerations.
Conclusion. An understanding of the
clinical and management issues involved
in preventing VTE is needed to improve
the use of anticoagulants and reduce the
incidence of VTE in health systems.
Index terms: Anticoagulants; Costs; Dosage;
Drugs; Formularies; Heparin; Hospitals; Kid-
ney diseases; Obesity; Protocols; Thrombocy-
topenia; Toxicity; Venous thromboembolism
Am J Health-Syst Pharm. 2010; 67(Suppl
6):S26-30
parinux, or a combination of one of
these pharmacologic methods with
optimally used intermittent pneu-
matic compression for patients un-
dergoing inpatient bariatric surgery.1

Discussion participants: Stuart T. Haines, Pharm.D., BCPS, FCCP,
FASHP, FAPhA, is Professor and Pharmacotherapy Specialist, Uni-
versity of Maryland School of Pharmacy, Baltimore, Maryland, and
Clinical Pharmacy Specialist, West Palm Beach VA Medical Center,
West Palm Beach, Florida. Dr. Haines reports that he has been a
stockholder (<$10,000) in Merck and that his spouse has served as a
consultant for Procter & Gamble.
William E. Dager, Pharm.D., BCPS, FCSHP, FCCP, FCCM, is
Pharmacist Specialist, University of California Davis Medical Cen-
ter; Clinical Professor of Pharmacy, University of California, San
Francisco, and Touro School of Pharmacy; and Clinical Professor of
Medicine, University of California, Davis, Sacramento, California.
Dr. Dager has disclosed no relevant financial relationship with a
commercial interest, as defined by the Accreditation Council for
Pharmacy Education (ACPE).
Toby C. Trujillo, Pharm.D., BCPS (AQ Cardiology), is Associ-
ate Professor, School of Pharmacy, University of Colorado Denver,
and Clinical Specialist—Cardiology/Anticoagulation, University of
Colorado Hospital, Aurora, Colorado. Dr. Trujillo reports that he has
served as a consultant for Ortho-McNeil.
Drs. Haines, Dager, and Trujillo received an honorarium from the
American Society of Health-System Pharmacists for their participa-
tion in the symposium and for their work on this article. This article
was developed with the assistance of a medical writer working with
ASHP Advantage. The medical writer, Susan R. Dombrowski, M.S.,
reports that she has no relevant financial relationship with a com-
mercial interest, as defined by ACPE. The authors approved the final
article and all its content.
Based on the proceedings of a symposium held December 8, 2009,
during the 44th ASHP Midyear Clinical Meeting and Exhibition
in Las Vegas, Nevada, and supported by an educational grant from
Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals,
Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC.
DOI 10.2146/ajhp100179

S26 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6

5b-Advantage_10-0179.indd 26 4/27/2010 3:00:55 PM


Larger-than-usual doses of UFH and
LMWH, with weight-based dosing of
LMWH, are recommended by ACCP
for these patients.2 However, the
ACCP guidelines do not provide de-
tailed guidance for choosing among
and dosing these anticoagulants in
obese patients like Mr. Vegas who
undergo bariatric surgery. Mr. Vegas
has a body mass index (BMI) of 58
kg/m2, making him morbidly obese
(a BMI >40 kg/m2 often is used to
define morbid obesity). What anti-
coagulant therapy would you use to
prevent VTE after bariatric surgery
in Mr. Vegas?
Dr. Dager: It would be important
to ascertain whether Mr. Vegas’s
DVT in 2006 was idiopathic or pro-
voked as the result of a precipitating
factor, such as a long airplane flight
or a surgical procedure. Neverthe-
less, Mr. Vegas is at higher risk for
VTE than other patients undergo-
ing bariatric surgery because of his
obesity and history of DVT. My
biggest concern is the increased risk
for pulmonary embolism because of
his obesity.
An effort to improve the diet and
lose weight prior to bariatric surgery
usually is recommended for patients
like Mr. Vegas. Enoxaparin 40 mg
subcutaneously (s.c.) every 12 hours
has been used successfully to prevent
VTE in patients undergoing bariat-
ric surgery for morbid obesity.3 We
perform a lot of bariatric surgery at
the University of California (UC)
Davis Medical Center. As improved
surgical techniques have led to
shorter lengths of stay and shorter
durations of VTE prophylaxis, we
subsequently observed an increase in
the incidence of VTE. Therefore, we
extended our dosing of enoxaparin
to 40 mg s.c. every 12 hours starting
preoperatively, and prophylaxis is
continued for at least seven days after
bariatric surgery. To date, we have
not observed any VTE complications,
which is consistent with a report in
which bariatric surgery patients who
received 3 days of prophylaxis had a
5b-Advantage_10-0179.indd 27
SYMPOSIUM  Clinical and management challenges
higher incidence of VTE compared
with patients who received enox-
aparin 30 mg s.c. every 12 hours for
10 days.4 Fondaparinux 2.5 mg s.c.
once daily is recommended by ACCP
for VTE prevention in nonobese
patients undergoing orthopedic or
other major surgery, and the drug
may have a therapeutic effect on
subclinical thrombosis that develops
during or after surgery.1 However,
the appropriate dose to use for obese
patients undergoing bariatric sur-
gery is unclear. Weight-based dos-
ing is used for VTE treatment, with
fixed daily 10-mg doses for patients
weighing more than 100 kg. A daily
5-mg dose might be considered for
VTE prophylaxis in Mr. Vegas, al-
though there is no evidence to sup-
port its use. This dose may be larger
than is required.
An aggressive unfractionated hep-
arin (UFH) regimen of 7500  units
s.c. every eight hours might be
considered for Mr. Vegas, although
evidence to support this regimen also
is lacking. When making the transi-
tion to warfarin therapy, a factor to
consider in choosing a warfarin dose
is the likelihood that Mr. Vegas may
respond differently than he did three
years ago. Therefore, use of the same
dose of warfarin that he received in
2006 may not be optimal.
Dr. Trujillo: I concur with
Dr. Dager. I would use enoxaparin
40 mg s.c. every 12 hours because of
the available evidence of its safety
and efficacy for VTE prevention after
bariatric surgery in the morbidly
obese patient population.3
Whether an aggressive UFH
dosing regimen is reasonable for
Mr. Vegas is unclear. At the University
of Colorado Hospital, we often have
difficulty determining the proper
dosage of UFH to use for VTE pro-
phylaxis in medically ill patients who
are obese. We typically use a dosage
based on weight extrapolated from
the Thromboembolism-Prevention
in Cardiac or Respiratory Disease
With Enoxaparin (PRINCE) trial.5
Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
In the PRINCE trial, a fixed UFH
dosage of 5000 units s.c. every eight
hours was used in medically ill pa-
tients, and approximately one third
of the patients were overweight. We
have no evidence to support our
approach to UFH dosing in medi-
cally ill patients who are obese,
however.
I might dose warfarin empirically,
titrating to an international nor-
malized ratio (INR) of 2.0 to 3.0 as
recommended by ACCP, rather than
using the 2006 dose.1 This approach
eliminates body weight as a consider-
ation in dosing.
Dr. Haines: Would you consider
using the activated partial throm-
boplastin time (aPTT) to guide
UFH dosing (e.g., a target aPTT of
40 seconds)? There is no evidence
to support this approach, but using
aPTT to guide therapy would at least
demonstrate that an anticoagulant
effect has been achieved.
Dr. Dager: At UC Davis Medical
Center, we might use aPTT values
to guide UFH dosing for VTE pro-
phylaxis in patients with advanced
age (e.g., 80 years or older) or a
low body weight (e.g., <50 kg). We
would check the aPTT periodically
to ensure that anticoagulation is not
excessive in these patients.
We have noticed that patients with
multiple acute traumas often are
antithrombin deficient during the
first few days after hospital admission,
which we have linked to increased
incidence of VTE and mortality in
critically ill trauma patients.6 We use
UFH infusions with a target aPTT of
35-45 seconds in trauma patients. We
have observed low DVT rates with
this approach, although it is not sup-
ported by clinical trial data.
In young pediatric patients, you
might consider the possibility of the
presence of a hypercoagulable state
due a hereditary deficiency in en-
dogenous anticoagulants.1 This pos-
sibility might need to be taken into
consideration in making decisions
about anticoagulant use or dosing
S27
4/28/2010 3:14:41 PM
 SYMPOSIUM  Clinical and management challenges
to prevent VTE in an obese pediatric
patient.
Clinical challenge 2
Dr. Haines: Mrs. Carson is a 63-
year-old woman who is admitted for
abdominal surgery for colon cancer.
She weighs 156 lb (71 kg). An epi-
dural catheter was placed for pain
control, but the surgeon would like
to remove it today (postoperative
day 1). Mrs. Carson has been receiv-
ing dalteparin 5000 units s.c. daily for
VTE prophylaxis since she is at high
risk because of her cancer and sur-
gery.1 Spinal hematoma formation
with long-term or permanent paraly-
sis is a rare complication of the use of
epidural catheters in anticoagulated
patients.1 Insertion and removal of
epidural catheters in patients receiv-
ing anticoagulants increases the risk
of this complication. When is the
best time to remove the catheter
from Mrs. Carson in relation to her
dalteparin therapy?
Dr. Trujillo: The timing of cath-
eter removal in Mrs. Carson is a
dilemma because of the need to
remove the catheter at a time when
the plasma concentration and thera-
peutic effect of dalteparin are low.
This is best done late in the dosing
interval but well before the next dose.
The dosing interval in Mrs. Carson is
24 hours, so catheter removal could
be recommended at least 12 hours
after a dose and 6 hours before the
next dose.
Dr. Dager: The strategy suggested
by Dr. Trujillo is reasonable. Another
approach to epidural catheter removal
in Mrs. Carson is to schedule it 22
hours after a dalteparin dose, which
will be 2 hours before the next dose.
There is no one best approach. Clini-
cal judgment should be used, and
institutional scheduling and staffing
issues need to be considered.
Clinical challenge 3
Dr. Haines: Mr. Genoa is a 58-
year-old man who is admitted for
exacerbation of congestive heart
S28 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
5b-Advantage_10-0179.indd 28
failure (CHF). During a previous
admission one month ago for CHF
exacerbation, he was given UFH
5000 units s.c. every eight hours for
VTE prophylaxis. His platelet count
had dropped from 260,000/µL to
130,000/µL at the time of discharge,
but no diagnostic testing for heparin-
induced thrombocytopenia (HIT)
was performed. What is the best
choice for anticoagulant therapy to
prevent VTE in Mr. Genoa now?
Dr. Dager: The UFH therapy
and 50% reduction in platelet count
during the previous hospitalization
suggests that HIT might have devel-
oped in Mr. Genoa, which increases
his risk for thromboembolism. The
platelet count should be checked.
The timing of suspected HIT only
one month ago creates a potential
risk for rapid-onset HIT if UFH or
LMWH is used now. Circulating
HIT antibodies formed during the
initial exposure to heparin will react
if heparin is administered within
100 days (especially within 30 days).6
The HIT antibodies formed during
UFH therapy often cross-react with
LMWH, eliminating this class of
agents as an option.7 Except for rare
circumstances, fondaparinux does
not cross-react with HIT antibod-
ies, so this drug may be one option
for VTE prophylaxis in patients like
Mr. Genoa with strongly suspected
or confirmed HIT.7 Warfarin alone
is not recommended for Mr. Genoa
if his platelet count is low because it
could increase the risk for thrombosis
and result in venous limb gangrene.7
Dr. Trujillo: I ag re e w ith
Dr.  Dager that it is important to
check Mr.  Genoa’s platelet count
now. The 260,000/µL or 130,000/µL
value measured one month ago could
have been a laboratory error.
If the oral direct thrombin (fac-
tor IIa) inhibitor dabigatran or oral
direct factor Xa inhibitor apixaban
or rivaroxaban were available, I
might consider using one of them. In
theory, these agents should not cross-
react with HIT antibodies, but this
has not yet been formally studied.
Moreover, clinical trials using these
new drugs for VTE prophylaxis in
medically ill patients like Mr. Genoa
have not yet been published.
I would probably use fonda-
parinux in Mr. Genoa, although I
would be concerned about the pos-
sibility that his CHF is severe enough
to cause significant renal impairment.
The elimination of fondaparinux is
prolonged and the risk for bleeding
is increased in patients with renal
impairment.8 The drug is contrain-
dicated in patients with severe renal
impairment (creatinine clearance
<30 mL/min). Therefore, I would
check Mr. Genoa’s renal function be-
fore initiating fondaparinux. I might
use a longer dosing interval (e.g., 48
hours) for Mr. Genoa, instead of the
customary 24-hour interval, if renal
dysfunction is present and no other
reasonable options exist.
Clinical challenge 4
Dr. Haines: Mrs. Minden is a
73-year-old woman who had hip
replacement surgery four days ago.
Fondaparinux 2.5 mg s.c. once daily
was started eight hours after surgery
for VTE prophylaxis. Mrs. Minden
will be discharged to a rehabilitation
facility today. For how long should
fondaparinux be continued?
Dr. Dager: The ACCP guidelines
recommend extended prophylaxis
for up to 35 days using LMWH, a vi-
tamin K antagonist, or fondaparinux
after total hip or knee replacement.1 I
recommend a longer duration (e.g.,
six weeks) of VTE prophylaxis after
hip replacement surgery for patients
like Mrs. Minden because VTE usu-
ally occurs later in this patient popu-
lation than in patients undergoing
total knee replacement surgery.9 She
could switch to warfarin and stop
fondaparinux once an INR of 2.0 to
3.0 is achieved, which is the range
recommended by ACCP and con-
sistent with most published studies
of patients undergoing hip or knee
replacement.1
4/27/2010 3:01:13 PM

Dr. Haines: I commonly see in-
jectable anticoagulants discontinued
when the INR exceeds 1.5 during
concomitant warfarin therapy for
VTE prophylaxis, an approach that
is not consistent with evidence-based
clinical practice guidelines. Studies
comparing the use of various INRs
for this transition have not been
conducted. I’m not sure how com-
fortable we should be with the use of
lower INRs.
Dr. Dager: I question the ad-
equacy of using the lower INR target
ranges (e.g., 1.5 to 2.0) for the transi-
tion to warfarin alone, as done by
some clinicians, although 1.5 to 3.0
was evaluated in one comparative
study of patients undergoing hip or
knee replacement.10 Of the other 14
comparative clinical trials in knee or
hip surgery, the lowest INR target was
1.8 and the highest was 3.0. I think a
compromise approach, with a target
INR of at least 1.8 and a maximum
of 3.0, could be considered.
Management challenge 1
Dr. Haines: The pharmacy and
therapeutics (P&T) committee at
Virginia City Hospital is evaluat-
ing several new anticoagulants—
apixaban, dabigatran, idraparinux,
and rivaroxaban—for addition to
the formulary. What considerations
should enter into the deliberations
and formulary decisions?
Dr. Trujillo: The safety, effective-
ness, ease of use, and cost of the new
agents compared with older agents
already on the formulary are pri-
mary concerns. Cost analyses should
take into consideration the costs of
managing adverse effects, particu-
larly bleeding and thromboembolic
events.
An oral route of administration
and infrequent dosing are associated
with ease of use. Idrabiotaparinux is
a biotinylated form of the indirect
factor Xa inhibitor idraparinux with
a long half-life that permits weekly
administration.11 It is given by s.c.
injection. The oral direct thrombin
5b-Advantage_10-0179.indd 29
SYMPOSIUM  Clinical and management challenges
inhibitor dabigatran and the direct
factor Xa inhibitors apixaban and
rivaroxaban are administered orally
once or twice daily. These oral agents
have a rapid onset of action, which
circumvents the need for bridge
therapy while waiting for a therapeu-
tic INR to be achieved before discon-
tinuing injectable anticoagulation
when warfarin is initiated for VTE
treatment.
Greater ease of use may be an
advantage of newer anticoagulants
over older agents. Their availability
may promote practitioner adher-
ence to VTE prophylaxis guidelines,
increase patient adherence to thera-
py, and ultimately lead to improved
effectiveness and outcomes. The
weight given to each consideration
will vary among health systems,
depending on their institutional
priorities and culture. Performance
and outcomes reporting and pay-
for-performance requirements per-
taining to anticoagulant use for VTE
prevention may influence formulary
decisions involving new anticoagu-
lants at Virginia City Hospital and
other institutions.
Management challenge 2
Dr. Haines: Dr. Henderson, a car-
diologist at Virginia City Hospital,
has requested the addition of dab-
igatran to the formulary for stroke
prevention in patients with atrial
fibrillation. The drug has been asso-
ciated with lower rates of stroke and
systemic embolism and similar rates
of major hemorrhage compared
with warfarin in this patient popu-
lation.12 Dr. Reno, an orthopedic
surgeon at the same institution, has
requested the addition of apixaban
to the formulary for VTE prevention
on the basis of limited safety and
efficacy data in patients undergoing
major orthopedic surgery.13,14 What
formulary additions should be made
at this institution at this time? The
acquisition costs of the drugs prob-
ably will be high. Should use of the
new agents be restricted to cases of
Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
therapeutic failure of less expensive
agents?
Dr. Trujillo: Decisions about add-
ing new anticoagulants to the formu-
lary depend on formulary openness,
P&T committee dynamics, and in-
stitutional characteristics and needs.
The introduction of new antico-
agulants will pose a dilemma to P&T
committees. I would not restrict the
use of new anticoagulants to cases of
therapeutic failure of established
agents, but I would restrict the pre-
scribing to specific physician groups
and indications to avoid widespread
use in patient populations in which
the drug may not yet have been
found safe and effective.
Dabigatran might be added to the
formulary for both stroke prevention
in patients with atrial fibrillation and
VTE prevention in patients undergo-
ing major orthopedic surgery. Safety
and efficacy data are available for use
of the drug in this surgical popula-
tion, although the efficacy data are
mixed.15-17
Published data are not yet avail-
able for the use of apixaban for stroke
prevention in patients with atrial
fibrillation. Therefore, its use should
be limited to VTE prevention in pa-
tients undergoing major orthopedic
surgery if the drug is added to the
formulary.
While not formally requested,
rivaroxaban should be considered
in conjunction with the requests by
Drs. Henderson and Reno at Virginia
City Hospital as part of a compre-
hensive review of the entire class of
medications. Published safety and
efficacy data are available for the use
of rivaroxaban for VTE prevention in
patients undergoing major orthope-
dic surgery.18-21 The formulary status
of new anticoagulants should be
re-evaluated as additional safety and
efficacy data become available.
Conclusion
Certain patients at risk for VTE
can present a clinical challenge. The
introduction of new anticoagulants
S29
4/27/2010 3:01:22 PM
 SYMPOSIUM  Clinical and management challenges
may pose a management challenge
in determining whether to add the
agents to the formulary and restrict
their use. The availability of new anti-
coagulants may help overcome some
clinical challenges in preventing VTE
and improve patient outcomes.
References
1. Geerts WH, Bergqvist D, Pineo GF et al.
Prevention of venous thromboembo-
lism: American College of Chest Physi-
cians evidence-based clinical practice
guidelines (8th edition). Chest. 2008;
133(6 Suppl):381S-453S.
2. Hirsh J, Bauer KA, Donati MB et al. Par-
enteral anticoagulants: American Col-
lege of Chest Physicians evidence-based
clinical practice guidelines (8th edition).
Chest. 2008; 133(6 Suppl):141S-59S.
3. Scholten DJ, Hoedema RM, Scholten SE.
A comparison of two different prophy-
lactic dose regimens of low molecular
weight heparin in bariatric surgery. Obes
Surg. 2002; 12:19-24.
4. Raftopoulos I, Martindale C, Cronin
A et al. The effect of extended post-
discharge chemical thromboprophylax-
is on venous thromboembolism rates
after bariatric surgery: a prospective
comparison trial. Surg Endosc. 2008;
22:2384-91.
5. Kleber FX, Witt C, Vogel G et al. Ran-
domized comparison of enoxaparin
with unfractionated heparin for the
prevention of venous thromboembolism
in medical patients with heart failure or
severe respiratory disease. Am Heart J.
2003; 145: 614-21.
6. Owings JT, Bagley M, Gosselin R et al.
Effect of critical injury on plasma an-
tithrombin activity: low antithrombin
levels are associated with thromboem-
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5b-Advantage_10-0179.indd 30
bolic complications. J Trauma. 1996;
41:396-405
7. Warkentin TE, Greinacher A, Koster
A et al. Treatment and prevention of
heparin-induced thrombocytopenia.
American College of Chest Physicians
evidence-based clinical practice guide-
lines (8th edition). Chest. 2008; 133(6
Suppl):340S-80S.
8. Arixtra package insert. Research Triangle
Park, NC: GlaxoSmithKline; 2009 Oct.
9. White RH, Romano PS, Zhou H et al.
Incidence and time course of throm-
boembolic outcomes following total hip
or knee arthroplasty. Arch Intern Med.
1998; 158:1525-31.
10. RD Heparin Arthroplasty Group. RD
heparin compared with warfarin for
prevention of venous thromboembolic
disease following total hip or knee ar-
throplasty. J Bone Joint Surg Am. 1994;
76:1174-85.
11. Harenberg J, Jorg I, Vukojevic Y et al. An-
ticoagulant effects of idraparinux after
termination of therapy for prevention
of recurrent venous thromboembolism:
observations from the van Gogh trials.
Eur J Clin Pharmacol. 2008; 64:555-63.
12. Connolly SJ, Ezekowitz MD, Yusuf S
et al. Dabigatran versus warfarin in
patients with atrial fibrillation. N Engl J
Med. 2009; 361:1139-51.
13. Lassen MR, Raskob GE, Gallus A et al.
Apixaban or enoxaparin for thrombo-
prophylaxis after knee replacement. N
Engl J Med. 2009; 361:594-604.
14. Lassen MR, Gallus AS, Pineo GF et
al. Late breaking clinical trial: the
ADVANCE-2 study: a randomized dou-
ble-blind trial comparing apixaban with
enoxaparin for thromboprophylaxis
after total knee replacement. J Thromb
Haemost. 2009;7(Suppl 2):abstract
LB-MO-005. Presented at the Interna-
tional Society on Thrombosis and Hae-
mostasis XXII Congress, Boston, MA:
July 13, 2009.
15. Ginsberg JS, Davidson BL, Comp PC et
al. Oral thrombin inhibitor dabigatran
etexilate vs North American enoxaparin
regimen for prevention of venous
thromboembolism after knee arthro-
plasty surgery. J Arthroplasty. 2009; 24:
1-9.
16. Eriksson BI, Dahl OE, Rosencher N et
al. Oral dabigatran etexilate vs. subcu-
taneous enoxaparin for the prevention
of venous thromboembolism after total
knee replacement: the RE-MODEL ran-
domized trial. J Thromb Haemost. 2007;
5:2178-85.
17. Eriksson BI, Dahl OE, Rosencher N et al.
Dabigatran etexilate versus enoxaparin
for prevention of venous thromboem-
bolism after total hip replacement: a ran-
domised, double-blind, non-inferiority
trial. Lancet. 2007; 370:949-56.
18. Eriksson BI, Borris LC, Friedman RJ et
al. Rivaroxaban versus enoxaparin for
thromboprophylaxis after hip arthro-
plasty. N Engl J Med. 2008; 358:2765-
75.
19. Kakkar AK, Brenner B, Dahl OE et al.
Extended duration rivaroxaban versus
short-term enoxaparin for the preven-
tion of venous thromboembolism after
total hip arthroplasty: a double-blind,
randomised controlled trial. Lancet.
2008; 372:31-9.
20. Lassen MR, Ageno W, Borris LC et al.
for the RECORD3 investigators. Rivar-
oxaban versus enoxaparin for thrombo-
prophylaxis after total knee arthroplasty.
N Engl J Med. 2008; 358:2776-86.
21. Turpie AG, Lassen MR, Davidson BL
et al. for the RECORD4 investigators.
Rivaroxaban versus enoxaparin for
thromboprophylaxis after total knee
arthroplasty (RECORD4): a randomised
trial. Lancet. 2009; 373:1673-80.
4/28/2010 3:15:42 PM

Continuing Education
Improving anticoagulant use
for prevention of venous
thromboembolism
Article #204-000-10-429-H01P
Knowledge-based activity
Qualifies for 2.5 hours (0.25 CEU) of continuing-education credit
Learning objectives
After studying these articles, the reader
should be able to
1. Describe the risk factors for venous
thromboembolism (VTE).
2. Explain the evolution of quality
improvement efforts as they pertain
to VTE prevention.
3. Describe strategies that health-system
pharmacists can use to close the
cultural gap between 20th- and
21st-century medicine and improve
anticoagulant use and outcomes in
patients at risk for VTE.
4. Identify a cause of difficulty in ­assessing
and reducing VTE risk, and  recom-
mend a strategy for the use of drug
therapy for VTE prophylaxis in a pa-
tient with unique characteristics that
require special consideration.
5. Discuss the shortcomings of cur-
rently available anticoagulants and
the characteristics of the ideal an-
ticoagulant, and compare and con-
trast the mechanisms of action,
pharmacokinetics, administration,
efficacy, safety, and potential for drug
interactions from currently available
and emerging anticoagulants for VTE
prevention.
6. Explain a clinical or management chal-
lenge associated with VTE ­prevention,
and outline a practical approach to
overcoming the challenge.
5b-Advantage_CE.indd 31
Continuing Education
Self-assessment questions
For each question there is only one best
answer.
1. Which of the following components
of Virchow’s triad does factor V
Leiden reflect?
a. A hypercoagulable state alone.
b. Endothelial injury alone.
c. Circulatory stasis alone.
d. Endothelial injury and circula-
tory stasis.
2. Which of the following is a risk
factor for venous thromboembo-
lism (VTE) commonly found in
hospitalized patients?
a. Diabetes mellitus.
b. Hyperlipidemia.
c. Peptic ulcer disease.
d. Prolonged immobility.
3. Which of the following is the most
important and therefore must
occur first in the quality-of-care
­continuum?
a. Clinical studies.
b. Evidence-based guidelines.
c. Mandatory practice and out-
comes reporting.
d. Pay-for-performance
requirements.
4. Which of the following parts of
the quality-of-care continuum
is represented by “never event”
reimbursement policies estab-
lished by the Centers for Medicare
and Medicaid Services for VTE
Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
after total hip or knee replacement
surgery?
a. Evidence-based guidelines.
b. Hospital/physician quality
measures.
c. Mandatory practice and out-
comes reporting.
d. Pay-for-performance
requirements.
5. Which of the following should
health-system pharmacists avoid in
order to improve the quality of care
and address the needs of patients at
risk for VTE?
a. Group decision making.
b. Multidisciplinary input.
c. Autonomous problem solving.
d. Teamwork.
6. Which of the following is a com-
mon reason for failure to adhere to
clinical practice guidelines for VTE
prophylaxis?
a. Excessive reliance on hema-
tologists to perform the risk
­assessment.
b. Excessive reliance on clinical
practice guidelines.
c. A lack of standardized methods
for measuring and defining
clinical trial outcomes.
d. A lack of awareness of the
­impact of VTE on morbidity
and mortality.
7. There is a lack of consensus among
health care practitioners and
controversy surrounds use of which
of the following drug therapies for
VTE prophylaxis?
a. Aspirin.
b. Low molecular weight heparin
(LMWH).
c. Unfractionated heparin (UFH).
d. Warfarin.
S31
4/28/2010 3:16:39 PM
 Continuing Education
8. Which of the following durations of
VTE prophylaxis is recommended
after total hip replacement surgery?
a. 1 week.
b. 6 weeks.
c. 10 weeks.
d. 6 months.
9. Which of the following enoxaparin
dosage adjustments should be made
for patients with morbid obesity
undergoing knee replacement
surgery?
a. The dosage should be decreased
to 20 mg every 24 hours.
b. The dosage should be decreased
to 30 mg every 24 hours.
c. The dosage should be increased
to 40 mg every 12 hours.
d. The dosage should be increased
to 50 mg every 12 hours.
10. For which of the following issues is
consensus lacking among clinicians
in the prevention of VTE?
a. The need to maintain the INR
during warfarin therapy between
2 and 3.
b. The need to avoid initiating
fondaparinux therapy less than
six hours after surgery.
c. The need for smaller-than-usual
LMWH doses in critically ill
patients.
d. The need to avoid removing an
epidural catheter during periods
of peak anticoagulant activity.
11. Which of the following statements
about the use of ultrasound screen-
ing for deep vein thrombosis before
hospital discharge of asymp-
tomatic patients after surgery
is correct?
a. It is routinely recommended
only after major orthopedic
surgery.
b. It is routinely recommended
only for morbidly obese patients.
S32 Am J Health-Syst Pharm—Vol 67 May 15, 2010  Suppl 6
5b-Advantage_CE.indd 32
c. It is routinely recommended
only for patients with severe
renal impairment.
d. It is not routinely recommended
for any patients.
12. Which of the following is a char-
acteristic of the ideal anticoagulant
for VTE prevention?
a. Narrow therapeutic index.
b. Irreversible action.
c. Oral route of administration.
d. Available in a single dosage
strength.
13. Which of the following is a new oral
vitamin K antagonist that is not
metabolized by cytochrome P-450
enzymes?
a. Apixaban.
b. Dabigatran etexilate.
c. Rivaroxaban.
d. Tecarfarin.
14. Which of the following is an
­emerging oral anticoagulant that
might interact with proton pump
inhibitors and other drugs that
lower gastric pH?
a. Apixaban.
b. Dabigatran etexilate.
c. Idrabiotaparinux.
d. Rivaroxaban.
15. Which of the following is an
­emerging oral anticoagulant that
might be particularly useful for
VTE prevention in patients with
renal impairment?
a. Apixaban.
b. Dabigatran etexilate.
c. Idrabiotaparinux.
d. Rivaroxaban.
16. Which of the following must be
considered in comparing the results
of clinical trials of oral direct
thrombin (factor IIa) and factor
Xa inhibitors for VTE preven-
tion in patients undergoing major
­orthopedic surgery?
a. Differences in the primary
­endpoint and comparator used.
b. Differences in the duration
of treatment and enoxaparin
­dosing regimen used.
c. Differences in the duration of
treatment and comparator used.
d. The results of clinical trials
should never be compared.
17. Which of the following statements
best characterizes the results of
­clinical trials of rivaroxaban for
VTE prevention in patients under-
going major orthopedic surgery?
a. The drug was superior in effi-
cacy to enoxaparin but increased
the risk for major bleeding.
b. The drug was superior in
­efficacy to enoxaparin without
increasing the risk for major
bleeding.
c. The drug was not inferior in
­efficacy to enoxaparin and was
not associated with an increased
the risk for major bleeding.
d. The drug was inferior to
­enoxaparin in terms of efficacy
and safety.
18. Which of the following best
­explains the finding that dabiga-
tran was inferior to enoxaparin
for VTE prevention in patients
undergoing total knee replacement
surgery in the RE-MOBILIZE
study but not in the RE-NOVATE
study?
a. Use of different dabigatran dos-
ages in the two studies.
b. Use of a shorter duration of
treatment in the RE-MOBILIZE
study.
c. Use of the more intense North
American enoxaparin dosing
regimen in the RE-MOBILIZE.
d. Concurrent use of aspirin with
dabigatran in the RE-NOVATE
study.
4/27/2010 3:02:15 PM

19. The use of anticoagulant therapy
for VTE prophylaxis is a concern
in surgical patients with epidural
catheters for postoperative analgesia
because of the risk of
a. Catheter-related sepsis.
b. Spinal hematoma.
c. Inadequate analgesia.
d. Thrombocytopenia.
20. Which of the following factors should
be considered and valued in mak-
ing formulary decisions about new
anticoagulants for VTE prophylaxis?
a. Cost.
b. Ease of use.
c. Efficacy and safety.
d. Safety, effectiveness, ease of use,
and cost.
5b-Advantage_CE.indd 33
Continuing Education
AJHP Continuing Education
Supplement: Improving anticoagu- Test for available tests, listed by topic
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