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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™
7PMVNFt/VNCFSt4VQQMFNFOU
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
S2 Introduction 4 &NFSHJOHBOUJDPBHVMBOUTGPSWFOPVT
Stuart T. Haines UISPNCPFNCPMJTNQSFWFOUJPO
Toby C. Trujillo
4 *NQSPWJOHUIFRVBMJUZPGDBSFGPSQBUJFOUT
BUSJTLGPSWFOPVTUISPNCPFNCPMJTN 4 $MJOJDBMBOENBOBHFNFOUDIBMMFOHFT
Stuart T. Haines JOQSFWFOUJOHWFOPVTUISPNCPFNCPMJTN
JOIFBMUITZTUFNT"DBTFCBTFEQBOFM
4 *TTVFTJOBTTFTTJOHBOESFEVDJOHUIFSJTL discussion
GPSWFOPVTUISPNCPFNCPMJTN Stuart T. Haines, William E. Dager, Toby C. Trujillo
William E. Dager
4 $POUJOVJOHFEVDBUJPO

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

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

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

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SYMPOSIUM  Improving the quality of care

References cians evidence-based clinical practice with cancer. J Clin Oncol. 2007; 25:
1. U.S. Department of Health and Human guidelines (8th edition). Chest. 2008; 5490-505.
Services. The Surgeon General’s Call to 133(6 Suppl):381S-453S. 6. American College of Obstetricians and
Action to Prevent Deep Vein Throm- 4. Agency for Healthcare Research and Qual- Gynecologists Committee on Practice
bosis and Pulmonary Embolism. 2008. ity. Preventing hospital-acquired venous Bulletins. ACOG Practice Bulletin No. 84:
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 / thromboembolism: a guide for effec- Prevention of deep vein thrombosis and
deepvein/calltoaction/call-to-action- tive quality improvement. August 2008. pulmonary embolism. Obstet Gynecol.
on-dvt-2008.pdf (accessed 2010 Jan 8). www.ahrq.gov/qual/vtguide/vtguide.pdf 2007; 110(2 Pt 1):429-40.
2. Hawkins D. Pharmacoeconomics of ­(accessed 2009 Dec 11). 7. American Academy of Orthopaedic
thrombosis management. Pharmaco- 5. Lyman GH, Khorana AA, Falanga A ­Surgeons. Clinical guideline on pulmo-
therapy. 2004; 24(7 pt 2):95S-99S. et al. American Society of Clinical nary embolism in patients undergoing
3. Geerts WH, Bergqvist D, Pineo GF et al. Oncolog y guideline: recommenda- total hip or knee arthroplasty. May 2007.
Prevention of venous thromboembo- tions for venous thromboembolism www.aaos.org/Research/guidelines/PE_
lism: American College of Chest Physi- prophylaxis and treatment in patients 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 Purpose. To describe risk factors for venous opment and implementation of VTE risk as-
physiologist, described the three thromboembolism (VTE), quality improve- sessment tools and treatment algorithms,
main types of abnormalities that ment efforts for VTE prevention, and strate- protocols, policies, and procedures are
gies health-system pharmacists can use to among the strategies that health-system
can result in thrombus (clot) for-
improve anticoagulant use and outcomes pharmacists can use to improve anticoagu-
mation in blood vessels: endothe- in patients at risk for VTE. lant use and quality of care in patients at
lial injury, circulatory stasis, and Summary. Risk factors for VTE involve risk for VTE.
hypercoagulable states. These three the presence of one or more components Conclusion. The use of anticoagulant ther-
abnormalities—known as Virchow’s of Virchow’s triad (endothelial injury, apy presents health-system pharmacists
triad—are the fundamental causes of circulatory stasis, and hypercoagulable with both challenges and opportunities to
venous thromboembolism (VTE).1 states) and are exceedingly common in improve the quality of care in patients at
hospitalized ­p atients. Several effective risk for VTE.
Virchow understood that injury to
methods for VTE prophylaxis are read-
the vascular endothelium (i.e., lining ily available but remain underused. Qual- Index terms: Anticoagulants; Hospitals;
of the inner wall of blood vessels) ity improvement initiatives to improve VTE Patient care; Pharmacists, hospital; Proto-
through trauma, surgery, or inser- prophylaxis rates include evidence-based cols; Quality assurance; Risk management;
tion of a catheter provokes a cascade clinical practice guidelines, mandatory Venous thromboembolism
of events, including fibrin formation practice and outcomes reporting, and pay- Am J Health-Syst Pharm. 2010; 67(Suppl
and platelet adhesion, and results in for-performance requirements. The devel- 6):S3-8
clot formation. He also recognized

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

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

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SYMPOSIUM  Improving the quality of care

that clots are more likely to form in heredity, genetic mutations, acquired erative recovery period. Major trauma
slow-moving blood than in blood diseases, or malignancy. from a motor vehicle accident or
that flows swiftly. The forces (i.e., Virchow understood the role gunshot results in endothelial injury;
pressures) that propel blood and the that the three phenomena—vessel surgical repair often is required, with
rate of blood flow are much lower injury, blood stasis, and circulating additional endothelial injury and im-
in the veins than in the arteries, so factors—play in the development mobilization during the procedure
spontaneous clot formation is more and propagation of clots. He reached and recovery period.
likely in the veins than in the arteries. this understanding without the ben- Patients with malignancy, a com-
A near cessation in blood flow (i.e., efit of electron microscopes, mass mon cause of hospitalization, are
stasis) alone can provoke clot forma- spectrometry, or enzyme-linked in a hypercoagulable state. Some
tion. Circulatory stasis and clots can immunosorbent assay. Today’s clini- malignancies (e.g., brain tumors;
occur during prolonged periods of cians can still use Virchow’s triad to adenocarcinomas of the lung, ovary,
immobility (e.g., in elderly patients identify patients at risk. pancreas, colon, stomach, prostate,
or air travelers). and kidney; and hematologic malig-
Virchow also was aware that some Identifying patients at risk nancies) are associated with a greater
people are more or less prone to Most hospitalized patients are at risk for VTE than are others.6 More-
clot formation than others because risk for VTE, but VTE prophylaxis is over, many cancer patients require
of hereditary deficiencies or genetic underutilized.2-5 Table 1 lists the ma- surgery, have indwelling catheters in
mutations (e.g., people with hemo- jor risk factors for VTE, and these risk place, and are frail and immobilized.
philia have a reduced tendency to clot factors reflect the presence of one or The risk for VTE is particularly high
because of a deficiency of clotting more components of Virchow’s triad. in patients who have metastatic dis-
factor VIII or IX). Clot formation is For example, patients undergoing ease and are receiving chemotherapy.
associated with numerous hyperco- major surgery experience endothelial Many patients with major medical
agulable states (i.e., thrombophilias) injury and are immobilized during illness (e.g., congestive heart fail-
characterized by excessive amounts and after the procedure. Patients ure, respiratory failure, myocardial
of procoagulant substances in the undergoing orthopedic procedures infarction, sepsis) are hospitalized.
circulation or deficiencies of en- involving a hip or knee are often inac- Venous stasis may develop during
dogenous anticoagulants caused by tive for several days during a postop- their hospitalization.
Increasing age is an indepen-
dent risk factor for VTE.6 Hospital-
ized medical and surgical patients
Table 1. typically are more than 40  years of
Risk Factors for VTE6,7,a age, and advanced age adds to the
risk for VTE associated with major
Major Risk Factors medical illness and surgery.
Major surgery (especially involving the hip, knee, or abdomen) A history of deep vein thrombo-
Major trauma sis (DVT) or pulmonary embolism
Malignancy (especially metastatic disease) (PE) often reflects the presence of
Major medical illness (e.g., CHF, MI, sepsis) a hypercoagulable state that places
Prolonged immobility (≥ 3 days)
patients at high risk for recurrence.6
Previous DVT/PE
DVT in the lower legs can damage
Increasing age (> 40 yr)
the venous valves and slow the rate
Contributing Risk Factors of return blood flow to the heart or
Thrombophilia/hypercoagulable states can result in retrograde flow in the
Antithrombin III deficiency affected vein. Partial venous obstruc-
Protein C or S deficiency
tion from the initial clot may persist,
Activated protein C resistance/Factor V Leiden
Prothrombin (20210) gene mutation
predisposing the patient to recurrent
Antiphospholipid antibodies thrombus formation.
Use of estrogens/raloxifene/tamoxifen Various contributing risk factors
Pregnancy/early post-partum period for VTE (Table  1) may be present
Obesity in hospitalized patients.7 Inherited
or acquired hypercoagulable states
CHF = congestive heart failure; DVT = deep vein thrombosis; MI = myocardial infarction; PE = pulmonary
embolism; VTE = venous thromboembolism are among the risk factors that may
a
This list is not inclusive. be present in hospitalized patients.6

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SYMPOSIUM  Improving the quality of care

The most common, factor V Leiden, ious organizations used the findings Other evidence-based clinical
is a genetic abnormality in coagula- of these studies to develop evidence- practice guidelines focus on specific
tion factor V that leads to activated based clinical practice guidelines for patient populations at risk for VTE.
protein C resistance (i.e., failure of prophylactic therapy in patients at For example, guidelines for VTE pre-
the natural anticoagulant protein C risk for VTE. As clinicians’ acceptance vention in patients with cancer are
to regulate clotting activity of factor of these guidelines increased, con- available from the American Society
V). An acquired hypercoagulable sensus standards of practice for pro- of Clinical Oncology, and guidelines
state commonly associated with au- viding patient care were developed. for women during pregnancy or the
toimmune disorders (e.g., systemic Organizations devoted to quality early postpartum period are available
lupus erythematosus, rheumatoid improvement began promulgating from the American College of Obste-
arthritis, Crohn’s disease) is the pres- the use of quality measures to ensure tricians and Gynecologists.9,10
ence of antiphospholipid antibodies. that standards of practice were met The American Academy of
Medications with estrogenic activity, and to assess hospital and physician Orthopaedic Surgeons (AAOS) Clini-
including estrogen-containing oral performance and patient outcomes. cal Guideline on Pulmonary Embolism
contraceptive tablets and skin patches, Over the past four or five years, it has in Patients Undergoing Total Hip Or
estrogen-replacement therapy, and become mandatory to report these Knee Arthroplasty is available on the
vaginal contraceptive rings that quality measures for comparison organization’s website, but it has not
contain estrogen, as well as estrogen among practitioners and facilities been published in a peer-reviewed
agonist–antagonists (i.e., selective and identification of those with journal.11 The AAOS document is
estrogen receptor modulators), can exemplary performance. Recently, controversial; it contains recommen-
provoke clot formation.6 The mecha- pay-for-performance requirements dations for the use of aspirin to pre-
nism is not entirely understood, have been established, with quality vent PE in orthopedic surgery that are
but estrogens are believed to in- goals and financial incentives and re- not consistent with the ACCP guide-
duce a hypercoagulable state in a wards for meeting those goals. lines. The ACCP guidelines recom-
dose-dependent manner. Pregnancy Perhaps the best known evidence- mend against the use of aspirin alone
and the early postpartum period based clinical practice guidelines for for VTE prevention in these patients.6
also are associated with an increased VTE prevention are those published Clinical practice guidelines require
risk for VTE, presumably because of by the American College of Chest the interpretation of evidence. The
the high levels of estrogen present at Physicians (ACCP) as part of a set recommendations and conclusions
those times. of guidelines regarding the use of drawn from the evidence may differ
Obesity increases the risk for antithrombotic and thrombolytic depending on the experience and
VTE, possibly from circulatory stasis therapy.6 These guidelines are up- values of the individuals writing the
caused by pressure from excessive dated periodically and released as a guidelines. Discrepancies among
body weight on the leg veins and supplement to the periodical Chest; guidelines from different sources
reduced venous return from the the most recent (8th) edition was often reflect conflicting opinions
lower extremities.6 The effect of obe- published in June 2008. The 2008 among experts.
sity also could be indirect through ACCP guideline for VTE prevention The clinical studies that are the
diminished physical activity and an is very comprehensive—72 pages source of evidence-based guidelines
increased risk for medical illnesses long, with 89 recommendations and often have stringent patient inclusion
that predispose patients to VTE (e.g., 728 references. The ACCP guidelines and exclusion criteria. Extrapolation
heart failure, osteoarthritis requiring are authoritative and provide a basis of the results of clinical studies to pa-
joint replacement surgery). for many of the guidelines and qual- tient populations that did not meet
ity improvement initiatives of other the inclusion criteria is inappropri-
Quality of care organizations. ate, but clinicians often must make
Emphasis on the quality of patient In August 2008, the Agency for well-reasoned inferences when data
care has increased over the years, and Healthcare Research and Quality regarding the best course of action
the use of practice guidelines and (AHRQ), a governmental organiza- are lacking.
quality measures has moved from tion, released Preventing Hospital- The processes used to develop and
voluntary to mandatory. Numerous Acquired Venous Thromboembolism: publish evidence-based guidelines
clinical studies over the past several A Guide for Effective Quality Improve- are time-consuming, often requiring
decades have evaluated the efficacy of ment.8 This publication relies heavily years. By the time guidelines are pub-
various nonpharmacologic and phar- on the ACCP guidelines, but it also lished, they may not reflect current
macologic interventions for prevent- addresses systems of care that should data. Nevertheless, evidence-based
ing VTE. In the mid to late 1980s, var- be implemented in hospitals. guidelines for VTE prophylaxis are

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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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SYMPOSIUM  Improving the quality of care

remains a top priority because of its approach reduces the isolation that Inservice education programs and
direct impact on patient outcomes. all too often inhibits potentially valu- electronic or print newsletters are
Other requirements are impor- able input for solving problems and possible methods for educating
tant (e.g., the use of oral unit dose improving clinical practices. Health- staff.
products, prefilled syringes, and system pharmacists in collaboration Quality metrics should be devel-
premixed infusion bags; obtaining with other members of the health oped and data collected in order to
a baseline international normalized care team can play an important assess institutional performance as
ratio prior to initiating warfarin role in creating cultural changes and well as provide ongoing feedback to
therapy; educating prescribers, staff, improving VTE prophylaxis prac- practitioners and teams. This feed-
patients, and family members), but tices. Developing hospitalwide or back can be used to identify weak-
continual efforts aimed at evaluating unit-specific treatment algorithms or nesses and opportunities for quality
and implementing institutionwide protocols, policies, and procedures improvement.
anticoagulation safety practices will for anticoagulant use is an impor-
likely have the greatest impact on tant undertaking. Topics that may Conclusion
patient outcomes. be addressed include anticoagu- Historically, implementing changes
lant selection (i.e., indications for to improve the quality of care has
Closing the gap use), dosing, duration of therapy, been a slow process. Quality im-
The culture of medicine has laboratory and clinical monitor- provement initiatives, mandated
undergone a gradual evolution over ing, adverse event management, practice and outcomes reporting,
the past several decades.21 In the mid- transition care (e.g., at the time of and pay-for-performance require-
20th century, health care typically transfer from an intensive care unit ments for VTE prophylaxis demand
was provided by individuals in solo to a medical floor), and hospital the attention of health-system phar-
practices who were autonomous and discharge planning. Standardized macists. The challenges associated
made decisions on the basis of their order sets for anticoagulants should with fulfilling these requirements
knowledge and experience. These be developed. represent an opportunity for health-
individuals carried considerable In order to achieve measurable and system pharmacists to collaborate
responsibility and were expected to meaningful improvements in quality, with other members of the health
be infallible, but continuous learning multiple strategies will be needed, care team to improve the use of anti-
was required to stay abreast of new including creating useful tools, edu- coagulants and the quality of care in
developments in medicine. cating practitioners, and providing patients at risk for VTE.
Modern 21st-century medical performance feedback. Several stud-
care is characterized by group prac- ies have shown that VTE prophylaxis References
tices in which teamwork with input rates improved at institutions that 1. Virchow R. Ueber die Erweiterung
kleinerer Gefäfse. Arch Pathol Anat
from members of various health developed and consistently used VTE Physiol Klin Med. 1851; 3:427-62.
care professions is used for prob- risk assessment tools and admission 2. Aujesky D, Guignard E, Pannatier A
lem solving and continuous qual- order sets. These tools can be paper- et  al. Pharmacological thromboembolic
prophylaxis in a medical ward: room for
ity improvement. The burden of based or automated through the use improvement. J Gen Intern Med. 2002;
decision-making is shared, because it of informatics (e.g., electronic risk- 17:788-91.
is understood that no one is infallible. scoring systems with alert capabili- 3. Amin A, Stemkowski S, Lin J et  al.
Thromboprophylaxis rates in US medi-
Modern medicine is a dynamic field, ties to identify high-risk patients, and cal centers: success or failure? J Thromb
with rapid changes brought about by computerized physician order entry Haemost. 2007; 5:1610-6.
the introduction of new information programs with standardized orders 4. Arnold DM, Kahn SR, Shrier I. Missed
opportunities for prevention of venous
and technologies. and links to treatment guidelines, thromboembolism: an evaluation of the
An appreciation of the limita- algorithms, and protocols).22-25 use of thromboprophylaxis guidelines.
tions of 20th-century medicine and The implementation of VTE risk Chest. 2001; 120:1964-71.
5. Yu HT, Dylan ML, Lin J et  al. Hospitals’
the need for alternative approaches assessment tools and treatment compliance with prophylaxis guidelines
to improve the quality of care and algorithms, protocols, policies, and for venous thromboembolism. Am J
patient outcomes in the 21st cen- procedures requires a comprehen- Health-Syst Pharm. 2007; 64:69-76.
tury provides impetus for identifying 6. Geerts WH, Bergqvist D, Pineo GF et al.
sive educational program for health Prevention of venous thromboembolism:
strategies for changing the health care practitioners, patients, and American College of Chest Physicians
care culture. These strategies may family members. Health care prac- evidence-based clinical practice guide-
include obtaining support from titioners should be informed about lines (8th edition). Chest. 2008; 133(6
Suppl):381S-453S.
institutional management and estab- the rationale for and the logistics 7. Francis CW. Clinical practice. Prophy-
lishing interprofessional teams. This of using any new tool or procedure. laxis for thromboembolism in hospital-

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SYMPOSIUM  Improving the quality of care

ized medical patients. N Engl J Med. 2007; Current+NHQM+Manual.htm (accessed 19. The Joint Commission. Preventing
356:1438-44. 2009 Dec 11). errors relating to commonly used an-
8. Agency for Healthcare Research and 14. Miller A, Roche LM. Surgical Care ticoagulants: applicable Joint Commis-
Quality. Preventing hospital-acquired Improvement Project: from SIP to sion standards. September 18, 2008.
venous thromboembolism: a guide for SCIP. November/December 2007. www. www.jointcommission.org/NewsRoom/
effective quality improvement. August medicarepatientmanagement.com/ PressKits/Preventing+Errors+Relating+
2008. www.ahrq.gov/qual/vtguide/ issues/02-06/mpmND07-SurgicalMiller. to+Commonly+Used+Anticoagulants/
vtguide.pdf (accessed 2009 Dec 11). pdf (accessed 2009 Dec 12). applicable_standards.htm (accessed 2009
9. Lyman GH, Khorana AA, Falanga A et al. 15. Surgical Care Improvement Project core Dec 12).
American Society of Clinical Oncology measure set. November 2008. www. 20. Rich DS. Update on the implementation
guideline: recommendations for venous jointcommission.org/Performance of the Joint Commission anticoagulation
thromboembolism prophylaxis and treat- Measurement/PerformanceMeasurement/ National Patient Safety Goal. Presented
ment in patients with cancer. J Clin Oncol. SCIP+Core+Measure+Set.htm (accessed at the ASHP Midyear Clinical Meeting
2007; 25:5490-505. 2009 Dec 11). and Exhibition; Rosemont, IL: June 15,
10. American College of Obstetricians and 16. Centers for Medicare & Medicaid Services. 2009. www.ashp.org/DocLibrary/Policy/
Gynecologists Committee on Practice Medicare and Medicaid move aggressively 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
Bulletins. ACOG Practice Bulletin No. 84: to encourage greater patient safety in hos- _Patient_Safety_Goal_Anticoag.pdf
Prevention of deep vein thrombosis and pitals and reduce never events. July 31, 2008. (accessed 2009 Dec 12).
pulmonary embolism. Obstet Gynecol. www.cms.hhs.gov/apps/media/press/ 21. Shine KI. Health care quality and how to
2007; 110(2 Pt 1):429-40. release.asp?Counter=3219&intNumPer achieve it. Acad Med. 2002; 77:91-9.
11. American Academy of Orthopaedic Page=10&checkDate=&checkKey=& 22. Dobesh PP, Stacy ZA. Effect of a clini-
Surgeons. Clinical guideline on pul- srchType=1&numDays=3500&srchOpt= cal pharmacy education program on
monary embolism in patients under- 0&srchData=&keywordType=All&chkN improvement in the quantity and quality
going total hip or knee arthroplasty. ewsType=1%2C+2%2C+3%2C+4%2C+ of venous thromboembolism prophylaxis
May 2007. www.aaos.org/Research/ 5&intPage=&showAll=&pYear=&year= for medically ill patients. J Manag Care
guidelines/PE_guideline.pdf (accessed &desc=false&cboOrder=date (accessed Pharm. 2005; 11:755-62.
2009 Dec  11). 2009 Dec 12). 23. Piazza G, Rosenbaum EJ, Pendergast W
12. Agency for Healthcare Research and 17. The Joint Commission. Accreditation et  al. Physician alerts to prevent symp-
Quality. Making health care safer: a program: hospitals. National patient tomatic venous thromboembolism in
critical analysis of patient safety practices. safety goals. Pre-publication version. hospitalized patients. Circulation. 2009;
Evidence Report/Technology Assessment, 2008. www.jointcommission.org/NR/ 119:2196-201.
No. 43. AHRQ Publication No. 01-E058, rdonlyres/31666E86-E7F4-423E-9BE8 24. Kucher N, Koo S, Quiroz R et al. Electron-
July 2001. www.ahrq.gov/clinic/ptsafety/ F05BD1CB0AA8/0/HAP_NPSG.pdf ic alerts to prevent venous thromboem-
(accessed 2009 Dec 11). (accessed 2009 Dec 11). bolism among hospitalized patients. N
13. The Joint Commission. Specifications 18. The Joint Commission. 2009 National Engl J Med. 2005; 352: 969-77.
manual for national hospital inpatient patient safety goals. www.jcrinc.com/ 25. Tooher R, Middleton P, Pham C et  al. A
quality measures, version 3.0c. www. common/PDFs/fpdfs/pubs/pdfs/JCReqs/ systematic review of strategies to improve
jointcommission.org/PerformanceMea JCP-07-08-S1.pdf (accessed 2009 Dec prophylaxis for venous thromboembolism
surement/PerformanceMeasurement/ 12). in hospitals. Ann Surg. 2005; 241:397-415.

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

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

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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

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SYMPOSIUM  Assessing and reducing the risk

(CMS) and various organizations to The need for and risks associated Regardless, a high risk for VTE is as-
reduce postoperative complications. with VTE prophylaxis in orthopedic sociated with lower-extremity ortho-
Receiving appropriate VTE prophy- surgery patients (i.e., the risks for pedic procedures unless prophylaxis
laxis in the period between 24 hours bleeding and thrombosis) change is provided. In the absence of VTE
before the anesthesia start time and over time and depend on the type of prophylaxis after knee replacement
24  hours after the anesthesia end orthopedic surgery. The risk for DVT surgery, the risk for proximal DVT
time is a required SCIP process mea- and bleeding is initially higher after is 5–22% and PE is 1.5–10%.5 After
sure.15 Multiple transfers, from the knee replacement surgery than after untreated hip replacement surgery,
operating room to recovery and ulti- hip replacement surgery.5 However, the risk for proximal DVT is 18–36%
mately to the ward, can create delays the risk for pulmonary embolism and the risk for PE is 0.9–28%.5
in the initiation of therapy. Perfor- (PE) is higher after hip surgery than Fatal PE poses the greatest con-
mance can be improved by having knee surgery, possibly because of the cern, regardless of the reason for
systems in place, such as electronic proximity of the hip to the lungs.5 hospitalization. The incidence in
alerts about the need to administer orthopedic surgery patients appears
VTE prophylaxis within this 24-hour Duration of prophylaxis to be low when prophylaxis is used
window after surgery. The duration of VTE prophylaxis (0.1%), although the true incidence
Considerations in planning or needed may depend on the period of of fatal PE is unknown because au-
evaluating the appropriateness of VTE risk benefiting from prevention. topsies in cases of sudden death often
VTE prophylaxis during the 24-hour This can be influenced by patient are not performed. 18 Asymptom-
period after surgery include whether characteristics (e.g., prolonged im- atic VTE confirmed by venography
heparin was used preoperatively mobility) and differs among medi- is much more common than fatal
and what therapy might have been cal patients and surgical patients PE, even when prophylaxis is used.18
used in the postanesthesia care unit and different types of surgeries. For Asymptomatic VTE is a concern be-
and surgical care unit. Mechanical example, older, obese patients may cause of the potential for long-term
thromboprophylaxis (i.e., GCS or require additional prophylaxis after consequences (e.g., postthrombotic
IPC) is an option for many patients surgery. In a retrospective study of syndrome characterized by persistent
at high risk for bleeding, but adher- orthopedic patients with VTE despite edema, pain, purpura, dermatitis,
ence to IPC is low.5 prophylaxis, the median time to VTE pruritus, cellulitis, and ulceration).19
The use of combination anti- diagnosis was significantly longer
coagulant therapy (e.g., injectable after total hip replacement surgery Warfarin
heparin during warfarin initiation) (17 days) than after total knee replace- Determining the appropriate tar-
may be a better choice than heparin ment surgery (7 days, p < 0.001).16 A get range for INR during prophylac-
alone to  provide adequate postop- longer duration of VTE prophylaxis tic warfarin therapy is a dilemma for
erative VTE prophylaxis in orthope- (six weeks) is now frequently used clinicians. The target range recom-
dic surgery patients, although this for patients undergoing total hip re- mended by ACCP for VTE treatment
approach to postoperative VTE pro- placement surgery than for patients as well as prophylaxis in most situa-
phylaxis is not evidence based. The undergoing total knee replacement tions is 2.0 to 3.0.5,20 This goal also is
presence of an epidural catheter for surgery (30 days). Trials involving recommended by ACCP during war-
administration of analgesics may be the newer anticoagulants dabigatran farin therapy in patients with atrial
a consideration in the initiation of and rivaroxaban have explored pro- fibrillation to decrease the risk of
warfarin because of concerns about phylaxis of 28–35 days and 35 days, cardioembolic stroke.21 The American
bleeding and spinal hematoma for- respectively.17 Academy of Orthopaedic Surgeons
mation, a rare but potentially devas- Knee and hip replacement surger- (AAOS) recommends a goal INR of
tating complication. In some cases, ies are invasive, traumatic procedures. 2.0 or less for prevention of PE in
a rapid rise in the international All three components of Virchow’s patients undergoing total hip or knee
normalized ratio (INR) from initial triad (endothelial injury, circulatory replacement.8 AAOS recommends
factor VII loss may lead to INR val- stasis, and a hypercoagulable state) warfarin therapy for two to six weeks
ues above 2 within 24 hours. For this are present and promote thrombus starting the night before, or after, hip
reason, clinicians may prefer to wait formation in patients undergoing or knee replacement surgery.8 How-
until the epidural catheter has been these surgeries. The amount of surgi- ever, the AAOS recommended range
­removed before starting ­warfarin.5 cal blood loss has diminished with is not as well supported by evidence
The use of peripheral nerve blocks newer surgical techniques, and this as are the ACCP guidelines.8 The goal
does not seem to warrant the same may reduce any delay in starting INR range used in most published
level of concern. prophylaxis and the risk for VTE. studies of patients undergoing hip

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SYMPOSIUM  Assessing and reducing the risk

or knee replacement is 2.0 to 3.0, istration process by a diagnostic In the Pulmonary Embolism Pre-
although lower ranges (e.g., 1.8 to procedure), hospitalized patients do vention (Pep) trial, a large, random-
2.5, 1.5 to 3.0) have been studied.22,23 not always receive their medications ized, placebo-controlled study of
However, the target range of 1.5 to at the proper times, although medi- patients undergoing hip or knee re-
2.0 has not been adequately studied. cation administration and dispens- placement or hip fracture surgery, as-
Limited data are available on the goal ing cabinet records might suggest pirin 160 mg/day for 35 days starting
INR range in patients undergoing otherwise. In evaluating the absence preoperatively significantly reduced
hip fracture surgery.24 of an INR response and adjustment the incidence of VTE by 36%, from
An INR greater than 1.8 with of the warfarin dose, the possibility, 2.5% with placebo to 1.6% with as-
warfarin therapy might reflect suf- albeit uncommon, that a patient did pirin (p = 0.0003).28 Both treatment
ficient anticoagulation to prevent or not receive or take his or her dose of groups received the study drug in
treat established subclinical throm- warfarin should be considered. combination with whatever prophy-
bosis in patients for whom bleeding Patient education can play a laxis was considered necessary. In-
concerns are present. A model for critical role in the success of warfarin terpretation of the Pep study results
warfarin dosing suggests that a target therapy after hospital discharge. The is complicated by the extensive use
INR range of 1.7 to 3.3 might be ac- proper timing of this education for of post-hoc analysis. Surprisingly, a
ceptable for patients at risk for VTE, surgical patients is important be- higher incidence of acute myocardial
although this model requires valida- cause they typically are in pain and infarction was observed in the aspi-
tion.25 However, according to ACCP, may be unable to retain information rin group than in the placebo group.
INR values less than the recom- and instructions provided during the Additional data are needed to resolve
mended range (2.0 to 3.0) may not early postoperative period. However, the controversy surrounding the use
provide adequate protection against waiting until hospital discharge to of aspirin alone for VTE prophylaxis
VTE, and such values do not neces- provide patient education is inadvis- in orthopedic surgery patients.
sarily reduce the risk of bleeding.5 able because of the high likelihood
Because of concern about spinal that the patient will be overwhelmed LMWH
hematoma formation in patients with information about other aspects The use of LMWH products
with epidural catheters, warfarin of home care. In planning patient for VTE prophylaxis is not always
initiation should be delayed for at education about warfarin and other straightforward, especially for pa-
least two hours after removal of the drug therapies that will be used at tients with certain unique needs. The
epidural catheter.5 The first INR home, coordination with other LMWH usually is initiated 12–24
measurement should not be taken members of the health care team, hours after hip or knee replacement
for at least 12 hours after warfarin particularly nurses, is wise. surgery, which is consistent with
initiation because of the lag time recommendations from both ACCP
before any effect on the INR in more Aspirin and AAOS. 5,8 Subsequent dosing
sensitive patients may occur.26 When There is a lack of consensus should be provided in accordance
the first dose is given the night before among orthopedic surgeons, chest with the manufacturer’s prescribing
or after surgery, the goal INR range physicians, and other practitioners information; the dosing interval usu-
usually is not reached until the third on the use of aspirin for VTE pro- ally is every 12–24 hours, although an
postoperative day or later.5 phylaxis. AAOS considers aspirin interval of 24 hours may be preferred
Several bedside factors should be alone an option for PE prophylaxis for long-term prophylaxis.
taken into consideration in providing in patients undergoing total hip or The effects of enoxaparin are in-
warfarin therapy for VTE prevention. knee replacement, especially patients creased in patients with severe renal
In the early postoperative period, at high risk for bleeding.8 The dosage impairment (i.e., creatinine clear-
fluid may be collected from drains recommended by AAOS is 325 mg ance <30 mL/min, which includes
implanted at the surgical site. The twice daily for six weeks starting the chronic kidney disease [CKD] stage
appearance of substantial amounts day of surgery, although 81 mg/day 4 or 5), and the risk of bleeding com-
of blood in the drainage container may be used if gastrointestinal symp- plications may be increased. Most of
may be a signal of transient sensitiv- toms develop.8 By contrast, ACCP the data driving this recommenda-
ity to warfarin or may suggest exces- recommends against the use of as- tion came from patients with CKD
sive bleeding and the need to watch pirin alone as thromboprophylaxis stage 3 or 4, not dialysis-dependent
the INR response and warfarin dose for any patient group.5 This grade CKD. Therefore, dosage reduction
accordingly. 1A recommendation is a strong one (e.g., decreasing the enoxaparin dose
For various reasons (e.g., inter- based on randomized trials with con- by 50% or increasing the dosing in-
ruption of the medication admin- sistent results.27 terval from 12 hours to 24 hours) is

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SYMPOSIUM  Assessing and reducing the risk

recommended when the creatinine There was no relationship between doses greater than 5000 units/day in
clearance (CrCl) is between 20 and bleeding and BMI. morbidly obese patients.
30 mL/min.20 Patients on hemodi- Two s.c. enoxaparin dosing regi- In a small analysis of VTE prophy-
alysis and those with CKD stage 5 mens were compared in a non- laxis with 40 mg of enoxaparin after
were excluded from clinical trials; randomized study of 481 patients total hip arthroplasty or total hip re-
therefore, dosing in this population undergoing bariatric surgery for placement, injection into the thigh in
remains unclear. Tinzaparin and morbid obesity.33 The first 92 pa- patients with a BMI over 25 kg/mm2
dalteparin appear safe to use without tients enrolled received 30 mg every was associated with a loss of anti-Xa
dosage adjustment or anti-factor Xa 12 hours, and the subsequent 389 pa- activity, compared with other sites.36
monitoring in patients with CrCl tients received 40 mg every 12 hours. Analysis of the results of these
that exceeds 20 mL/min.30,31 Early ambulation, GCS, and IPC and other studies has led some clini-
Although four to six weeks of were used in both groups. The two cians to recommend increasing the
VTE prophylaxis appears warranted groups had a similar BMI (51.7 kg/ dosages of LMWH used for VTE
after total hip and knee replacement m2 for the first group and 50.3 kg/m2 prophylaxis in patients with morbid
surgery, the ACCP guidelines recom- for the second group). The duration obesity (i.e., a BMI of 40 kg/m2 or
mend VTE prophylaxis with LMWH of the procedure decreased over time higher) by 30% over dosages used for
for at least 10 days and extended pro- suggeting a potiential bias in favor nonobese patients.29 Clinical practice
phylaxis for up to 35 days for patients of the 40-mg cohort. The incidence guidelines have yet to include such a
undergoing hip or knee replacement of postoperative DVT complications recommendation.
surgery or hip fracture surgery.5,16 was significantly lower (0.6%) in the The efficacy of LMWH for VTE
The recommended duration of second group (the group receiving prophylaxis may be diminished in
LMWH in the AAOS guidelines is the larger enoxaparin dosage) than in critically ill patients in the intensive
7–12 days.8 As part of the preop- the first group (5.4%, p < 0.01). One care unit (ICU) because of anti-
erative evaluation, selection of the patient in each group required treat- thrombin deficiency, fluid overload,
pharmacologic agent to be used after ment for hemorrhage (i.e., the larger edema, or other factors.37-39 In 89 ICU
discharge should take into consider- enoxaparin dose was not associated patients, therapeutic anti-factor Xa
ation the costs and available options with an increased risk for bleeding). levels (0.1–0.3 IU/mL) were achieved
on the patient’s insurance plan so However, duration is another con- 4 hours, 12 hours, and 24 hours after
that authorization can be obtained, sideration. In a single practitioner’s a 40-mg s.c. dose of enoxaparin in
if needed. report of experience with 308 con- 56.5%, 39.3% and 12.6% of the pa-
Dosing of LMWH products in pa- secutive bariatric surgery patients, tients, respectively.38
tients with obesity has been studied the incidence of thromboembolism The pharmacokinetics and phar-
because of concerns about a poten- was significantly higher in patients macodynamics of enoxaparin 30 mg
tially increased risk for VTE due to who received 3 days (4.5%) of pro- s.c. every 12 hours were compared in
inadequate prophylaxis when fixed phylaxis than in those who received two cohorts of critically ill patients
doses of LMWH are used in this pa- 10 days (0%) of prophylaxis. The suffering from multiple trauma with
tient population. In a retrospective, patients’ mean BMI was 47 kg/mm2, or without a 10-kg or greater increase
multicenter study, 817 orthopedic and the enoxaparin dose was 30 in body weight due to peripheral ede-
surgery patients received fixed sub- mg twice daily for the duration of ma.37 The area under the curve (AUC)
cutaneous (s.c.) doses of enoxaparin hospitalization (approximately two for plasma anti-factor Xa activity
40 mg/day starting 12 hours before to three days) and 40 mg once daily over the 12-hour period after a dose
surgery. 32 The incidence of VTE after discharge.34 was highly variable in both groups.
detected with bilateral venography A subgroup analysis of the Pro- The 12-hour AUC, peak plasma anti-
during postoperative days 7–10 was spective Evaluation of Dalteparin factor Xa activity, and antithrombin
18.7%. There was no relationship Efficacy for Prevention of VTE in activity were significantly lower in
between body weight or body surface Immobilized Patients (Prevent) the patients with edema than in those
area and thrombosis, but there was trial, which compared dalteparin without edema (p < 0.05).
a strong relationship between body 5000 units/day with placebo, dem- Another study compared a group
mass index (BMI) and thrombosis onstrated no difference in outcomes of 16 ICU patients with a group of
(p  = 0.0002). The incidence of VTE between obese (BMI 34  ±  5 kg/m2, n 13 noncritically ill medical patients.39
was 31.8% in patients with a BMI = 1118) and non-obese (BMI 25  ±  4 The AUC for anti-factor Xa activ-
exceeding 32 kg/m2 (i.e., obese pa- kg/m2, n = 2563) subjects.35 Additional ity over the 12-hour period after
tients) and 16.7% in patients with a information is needed to determine a 40-mg s.c. dose of enoxaparin
BMI less than 32 kg/m2 (p < 0.001). the possible benefit of dalteparin was significantly lower in the ICU

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SYMPOSIUM  Assessing and reducing the risk

patients than in the noncritically ill In August 2009, the Food and of HIT-type reactions and throm-
medical patients (p = 0.008).39 Drug Administration (FDA) issued a bosis have been reported in patients
warning not to administer the initial receiving fondaparinux.48 The direct
Fondaparinux fondaparinux dose earlier than six to thrombin inhibitors typically are the
The use of fondaparinux for VTE eight hours after surgery because of initial anticoagulants used in the set-
prophylaxis can be problematic the risk of bleeding.44, 45 Spinal hema- ting of HIT. One treatment option
in certain settings secondary to its toma formation is a concern during that is currently available for prophy-
extended duration of activity and the insertion of epidural catheters in laxis in patients with a recent history
potential for a higher level of anti- patients receiving fondaparinux (or of HIT might be lepirudin admin-
coagulant effect. ACCP recommends other anticoagulants), so the drug istered subcutaneously.47 Emerging
(grade 1A) fondaparinux 2.5 mg s.c. should be discontinued sufficiently anticoagulants that may prove useful
once daily starting six to eight hours in advance of the placement of an in patients with HIT include the oral
after or the next day after hip fracture epidural catheter.5 The anticoagulant direct factor Xa inhibitor rivaroxa-
surgery and other major orthopedic effect of fondaparinux can persist ban and desirudin, a direct thrombin
surgeries.5 The dosing used for VTE for two to four days after the drug is inhibitor given by s.c. injection.49,50
prophylaxis may have a therapeutic discontinued.46 The cost of using these agents is cur-
effect on subclinical thrombosis that rently unknown until available.
develops during surgery. In a meta- Heparin-induced The reported risk for HIT is high-
analysis of four studies comparing thrombocytopenia est among patients undergoing or-
the efficacy of fondaparinux 2.5 mg Heparin-induced thrombocy- thopedic, cardiac, and vascular sur-
s.c. once daily with s.c. enoxaparin topenia (HIT) is a rare immune- gery who receive UFH for one to two
30 mg twice daily or 40 mg once mediated adverse effect associated weeks.47 When examining a consecu-
daily for preventing VTE in patients with LMWH and UFH therapy that tive series of 146 patients with suf-
undergoing major hip or knee sur- clinicians need to be aware of be- ficient suspicion of HIT for initiating
gery, the incidence of VTE confirmed cause it increases the risk for throm- a direct thrombin inhibitor at UC
by venography (i.e., asymptomatic bosis.47 The risk for HIT depends on Davis Medical Center, HIT was not
VTE) was significantly lower with the duration of heparin exposure found in any orthopedic patients.51
fondaparinux (6.8%) than with and the dosage used. The condition During this period, none of the more
enoxaparin (13.7%, p < 0.001).18 In typically develops if heparin therapy than 900 orthopedic surgery patients
Phase II fondaparinux dose-finding is continued for a week or longer. It who received a short course of UFH
clinical trials, no significant differ- also may develop later if the patient while transitioning to warfarin de-
ences in outcomes were observed is re-exposed to heparin within 100 veloped HIT.51 The lack of HIT with
with daily doses ranging from 2.5 days, especially within one month. the use of heparin in this population
mg to 12 mg in patients with acute Whether VTE in a patient discharged was attributed to the short-term use
coronary syndrome or 5 mg to 10 from the hospital receiving heparin of UFH and transition to warfarin
mg in patients with established for VTE prevention represents HIT for a minimum of one month for
VTE.40,41 Results in the OASIS 5 trial or failure of prophylaxis (e.g., nonad- prophylaxis.
showed no difference between 2.5 herence) can be difficult to ascertain.
mg of fondaparinux and 1 mg/kg In delayed-onset HIT, thrombocy- Surveillance ultrasound
twice-daily warfarin.42 In obese and topenia may occur up to 40 days The use of ultrasound screening
nonobese patients receiving fonda- after heparin therapy is discontinued. for DVT after orthopedic surgery has
parinux for the treatment of VTE Given the potential for VTE to occur been suggested as a way of identify-
(i.e., to prevent VTE recurrence), after discharge, the platelet count ing patients for treatment. The clini-
which involves fixed 10-mg doses for should be checked in any patient cal usefulness of such screening was
patients weighing more than 100 kg , with VTE after recent surgery. If evaluated in a study of 346 patients
the incidence of bleeding decreased more than 100 days has elapsed since undergoing hip or knee replace-
as weight increased.43 However the heparin therapy was administered, ment surgery followed by 10 days of
efficacy of the drug in preventing the risk for VTE is similar between LMWH therapy.52 Patients were ran-
VTE recurrence was not diminished heparin-naïve patients and those domly assigned to receive prolonged
by an increase in weight. These ob- with a history of HIT. prophylaxis with LMWH for an ad-
servations support the theory that The development of HIT requires ditional three weeks or postoperative
prophylactic dosing of fondaparinux discontinuation of heparin. Fonda- ultrasound screening for proximal
for prevention of VTE has a potential parinux is one option that has been and distal thrombosis. Therapeutic
therapeutic antithrombotic effect. used to treat HIT, although rare cases anticoagulation was provided to pa-

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SYMPOSIUM  Assessing and reducing the risk

tients in whom thrombosis was de- oratory values alone has limitations 8. American Academy of Orthopaedic
Surgeons. Clinical guideline on pulmo-
tected by screening, but patients with and is insufficient; input is needed nary embolism in patients undergoing
negative screening results did not from clinicians who can make pa- total hip or knee arthroplasty. May 2007.
receive additional LMWH therapy tient assessments at the bedside. www.aaos.org/Research/guidelines/PE_
guideline.pdf (accessed 2009 Dec 11).
after day 10. The incidence of symp- 9. Ozbudak O, Erogullari I, Ogus C et al.
tomatic VTE 35 days after hip or knee Conclusion Doppler ultrasonography versus venog-
replacement surgery was 4.3% with Clinicians face a variety of chal- raphy in the detection of deep vein
thrombosis in patients with pulmonary
prolonged prophylaxis and 2.3% lenges in identifying patients at risk embolism. J Thromb Thrombolysis. 2006;
with screening, a difference that was for VTE and devising prophylactic 21:159-62.
not significant (p = 0.37). Screening strategies. Patients at risk for VTE are 10. Oster G, Ollendorf DA, Vera-Llonch M
et al. Economic consequences of venous
did not reduce the rate of symptom- a heterogenous group with diverse thromboembolism following major
atic VTE over the subsequent three- characteristics and needs, and many orthopedic surgery. Ann Pharmacother.
month follow-up period. questions remain about the optimal 2004; 38:377-82.
11. Caprini JA. Thrombosis risk assessment
Guidelines from ACCP recom- pharmacotherapeutic approach to as a guide to quality patient care. Dis
mend against the routine use of meet their needs. Health-system Mon. 2005; 51:70-8.
ultrasound screening for DVT before pharmacists can improve outcomes 12. Lutz L, Haas S, Hach-Wunderle V et al.
Venous thromboembolism in internal
hospital discharge of asymptomatic in patients at risk for VTE by gain- medicine: risk assessment and phar-
patients after major orthopedic sur- ing an understanding of the issues maceutical prophylaxis: publication for
gery (grade 1A) because ultrasound involved in patient assessment and the specialist platform. Med Welt. 2002;
53:231-4.
screening is unreliable.5 Moreover, prophylactic drug therapy and by us- 13. Khorana AA, Kuderer NM, Culakova E et
positive ultrasound test results could ing evidence-based clinical practice al. Development and validation of a predic-
affect institutional performance guidelines and their clinical expertise tive model for chemotherapy-associated
thrombosis. Blood. 2008; 111:4902-7.
reports on Joint Commission and to advise other members of the care 14. Francis CW. Clinical practice. Prophy-
National Quality Forum core per- team about the proper use of drug laxis for thromboembolism in hospital-
formance measures and SCIP out- therapies for VTE prophylaxis. ized medical patients. N Engl J Med. 2007;
356:1438-44.
come measures. Further, they could 15. Miller A, Roche LM. Surgical Care
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Health-Syst Pharm. 2007; 64:69-76. al. Fondaparinux vs enoxaparin for the
basis of risk factor assessment. The 5. Geerts WH, Bergqvist D, Pineo GF et al. prevention of venous thromboembo-
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for surgeons primarily in the early American College of Chest Physicians meta-analysis of 4 randomized double-
evidence-based clinical practice guide- blind studies. Arch Intern Med. 2002;
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ing during this period is a challenge. 6. Lyman GH, Khorana AA, Falanga A et al. The clinical course of deep-vein throm-
American Society of Clinical Oncology bosis. Prospective long-term follow-up
Health-system pharmacists should guideline: recommendations for venous of 528 symptomatic patients. Haemato-
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2007; 25:5490-505. tithrombotic therapy for venous throm-
VTE, especially for patients with 7. American College of Obstetricians and boembolic disease. American College of
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sity, epidural catheters, or HIT and pulmonary embolism. Obstet Gynecol. 21. Fuster V, Rydén LE, Cannom DS et al.
critically ill patients). Managing lab- 2007; 110(2 Pt 1):429-40. ACC/AHA/ESC 2006 guidelines for the

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SYMPOSIUM  Assessing and reducing the risk

management of patients with atrial fibril- derly patients treated with tinzaparin novel synthetic compound (SR90107A/
lation: a report of the American College of (Innohep) administered once daily (175 ORG31540) with pure anti-factor Xa ac-
Cardiology/American Heart Association anti-Xa IU/kg): anti-Xa and anti-IIa tivity: a phase II evaluation. Circulation.
Task Force on Practice Guidelines and the activities over 10 days. Thromb Haemost. 2000; 102:2726-31.
European Society of Cardiology Com- 2000; 84:800-4. 42. Fifth Organization to Assess Strategies in
mittee for Practice Guidelines (Writing 31. Cestac P, Bagheri H, Lapeyre-Mestre M et Acute Ischemic Syndromes Investigators,
Committee to Revise the 2001 Guidelines al. Utilisation and safety of low molecular Yusuf S, Mehta SR, Chrolavicius S et al.
for the Management of Patients With weight heparins: prospective observa- Comparison of fondaparinux and enox-
Atrial Fibrillation): developed in collabo- tional study in medical inpatients. Drug aparin in acute coronary syndromes. N
ration with the European Heart Rhythm Saf. 2003; 26:197-207. Engl J Med. 2006; 354:1464-76.
Association and the Heart Rhythm Soci- 32. Samama MM, Verhille C, Carchy L. 43. Davidson BL, Buller HR, Decousus H et
ety. Circulation. 2006; 114:e257-354. Relation between weight, obesity, and al. Effect of obesity on outcomes after
22. Robinson KS, Anderson DR, Gross M frequency of deep venous thrombosis fondaparinux, enoxaparin, or heparin
et al. Ultrasonographic screening be- after enoxaparin in orthopedic surgery. treatment for acute venous thromboem-
fore hospital discharge for deep venous Thromb Haemost. 1995; 73:977. Abstract bolism in the Matisse trials. J Thromb
thrombosis after arthroplasty: the post- 300. Haemost. 2007; 5:1191-4.
arthroplasty screening study. A random- 33. Scholten DJ, Hoedema RM, Scholten SE. 44. U.S. Food and Drug Administra-
ized, controlled trial. Ann Intern Med. A comparison of two different prophy- tion. Arixtra (fondaparinux sodium)
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23. Dager W, King J, Meehan J et al. Clinical weight heparin in bariatric surgery. Obes Safety/MedWatch/SafetyInformation/
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ated heparin and warfarin after elective 34. Raftopoulos I, Martindale C, Cronin A et 45. Arixtra package insert. Research Triangle
total hip or total knee arthroplasty. Pre- al. The effect of extended post-discharge Park, NC: GlaxoSmithKline; 2009 Oct.
sented at the American College of Clinical chemical prophylaxis on venous throm- 46. Nutescu E, Dager W. Heparin, low molec-
Pharmacy 2006 Spring Practice and Re- boembolism rates after bariatric surgery: ular weight heparin, and fondaparinux.
search Forum. Monterey, CA: April 9–12, a prospective comparison trial. Surg In: Managing anticoagulation patients
2006. Abstract 48. www.pharmacotherapy . ­Endosc. 2008; 22:2834-91. in the hospital. Bethesda, MD: American
org/pdf/ACCP-Spring_Abstracts_2006. 35. Kucher N, Leizorovicz A, Vaitkus PT et Society of Health-System Pharmacists;
pdf (accessed 2009 Dec 13). al. Efficacy and safety of fixed low-dose 2007:177-202.
24. Powers PJ, Gent M, Jay RM et al. A dalteparin in preventing venous throm- 47. Warkentin TE, Greinacher A, Koster A et
randomized trial of less intense postop- boembolism among obese or elderly al. Treatment and prevention of heparin-
erative warfarin or aspirin therapy in the hospitalized patients: a subgroup analysis induced thrombocytopenia. American
prevention of venous thromboembolism of the prevent trial. Arch Intern Med. College of Chest Physicians evidence-
after surgery for fractured hip. Arch In- 2005;165:341-5. based clinical practice guidelines (8th
tern Med. 1989; 149:771-4. 36. Hacquard M, Mainard D, de Maistre E et edition). Chest. 2008; 133(6 Suppl):340S-
25. Rose AJ, Ozonoff A, Berlowitz DR et al. Influence on injection site of prophy- 80S.
al. Warfarin dose management affects lactic dose enoxaparin bioavailability in 48. Grouze E, Kryriakou E, Panagou I et al.
INR  control. J Thromb Haemost. 2009; obese patients. J Thromb Haemost. 2007; Fondaparinux for the treatment of acute
7:94-101. 5(Suppl 2):P-M-669. heparin induced thrombocytopenia:
26. Neel S. Essential warfarin knowledge. In: 37. Haas CE, Nelsen JL, Raghavendran K a single-center experience. Clin Appl
Managing anticoagulation patients in et al. Pharmacokinetics and pharmacody- Thromb Hemost. 2009; Oct 13 [epub
the hospital. Bethesda, MD: American namics of enoxaparin in multiple trauma ahead of print].
Society of Health-System Pharmacists; patients. J Trauma. 2005; 59:1336-43. 49. Walenga JM, Prechel M, Jeske WP et al.
2007:133-75. 38. Mayr AJ, Dünser M, Jochberger S et al. Rivaroxaban—an oral, direct Factor Xa
27. Guyatt GH, Cook DJ, Jaeschke R et al. Antifactor Xa activity in intensive care inhibitor—has potential for the manage-
Grades of recommendation for anti- patients receiving thromboembolic ment of patients with heparin-induced
thrombotic agents: American College of prophylaxis with standard doses of enox- thrombocytopenia. Br J Haematol. 2008;
Chest Physicians evidence-based clinical aparin. Thromb Res. 2002; 105:201-4. 143:92-9.
practice guidelines (8th edition). Chest. 39. Priglinger U, Delle Karth G, Geppert A 50. Matthai WH Jr. Treatment of heparin-
2008; 133(6 Suppl):123S-31S. et al. Prophylactic anticoagulation with induced thrombocytopenia in cardiovas-
28. Prevention of pulmonary embolism and enoxaparin: is the subcutaneous route cular patients. Expert Opin Pharmacother.
deep vein thrombosis with low dose as- appropriate in the critically ill? Crit Care 2006; 7:267-76.
pirin: Pulmonary Embolism Prevention Med. 2003; 31:1405-9. 51. Dager WE, Lee A, Gosselin RC et al.
(PEP) trial. Lancet. 2000; 355:1295-302. 40. Simoons ML, Bobbink IW, Boland J et ­E xploring adult patient populations
29. Nutescu EA, Spinler SA, Wittkowsky A al. A dose-finding study of fondaparinux at risk for developing HIT. J Thromb
et al. Low-molecular-weight heparins in in patients with non-ST-segment el- ­Haemost. 2007; 5(S2) P-T-329.
renal impairment and obesity: available evation acute coronary syndromes: the 52. Schmidt B, Michler R, Klein M et al.
evidence and clinical practice recom- Pentasaccharide in Unstable Angina ­U ltrasound screening for distal vein
mendations across medical and surgi- (PENTUA) Study. J Am Coll Cardiol. thrombosis is not beneficial after ma-
cal settings. Ann Pharmacother. 2009; 2004; 43:2183-90. jor orthopedic surgery. A randomized
43:1064-83. 41. The Rembrandt Investigators. Treatment controlled trial. Thromb Haemost. 2003;
30. Siguret V, Pautas E, Fevrier M et al. El- of proximal deep vein thrombosis with a 90:949-54.

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SYMPOSIUM  Emerging anticoagulants

Emerging anticoagulants for venous


thromboembolism prevention
Toby C. Trujillo

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

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

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SYMPOSIUM  Emerging anticoagulants

tween the American Academy of Evolution of anticoagulants Low molecular weight heparin
Orthopaedic Surgeons 2 (AAOS) Many advances have been made (LMWH) products were introduced
and American College of Chest in anticoagulant therapy since the in the 1980s, and direct thrombin
Physicians 3 (ACCP) recommen- 1930s and 1940s when unfractionated inhibitors (DTIs; e.g., argatroban,
dations for prevention of throm- heparin (UFH) and the vitamin K lepirudin, bivalirudin) and the pen-
boembolic disorders in major antagonist warfarin were the primary tasaccharide fondaparinux became
orthopedic procedures. Although options for treating patients.4 Most of available in the 1990s. These drugs
it is appropriate to question the these advances have resulted from ef- overcame many of the disadvantages
methodological soundness of the forts to overcome the shortcomings of of UFH and may be the preferred
AAOS guidelines, it is also appro- UFH and warfarin and focus on more agents in many clinical circum-
priate to recognize the importance specific targets in the coagulation stances. However, they still require
of incorporating the perspective of cascade to improve safety, efficacy, intravenous (i.v.) or subcutaneous
the operating physician into deci- and convenience. The shortcomings (s.c.) administration, are more costly
sions about VTE prevention for of these older agents include a nar- than UFH, and, depending on the
individual patients and the devel- row therapeutic index, unpredictable specific agent, may be contraindicated
opment of a standard approach at a pharmacokinetics and pharmacody- or difficult to use in patients with
health care institution. Orthopedic namics (i.e., dose-response relation- hepatic or renal dysfunction. New
surgeons are now focusing more on ship), need for laboratory monitoring, anticoagulants under development
VTE prevention than they have in and risk for bleeding. Warfarin, which may provide advantages over the cur-
the past, in part because of the need is administered orally, provides some rent injectable agents and warfarin.
for accountability to accreditation advantages over injectable antico- Desirudin, an injectable DTI, has
and governmental groups for VTE agulants. However, warfarin exhibits been approved for VTE prevention in
as an outcome in their patients. complex pharmacokinetics and phar- orthopedic surgery since 2003. Com-
New anticoagulant options for VTE macodynamics and interacts with pared with other DTIs, desirudin will
prevention will need to take into many medications and foods. These likely be available in a dosage form
consideration the priorities of all issues, along with patient nonadher- that is more amenable with VTE
parties caring for patients at risk ence, make the drug less than ideal in prevention. New oral agents have
for VTE. many circumstances. 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.
Figure 1. Current anticoagulant options. Adapted from Kubitza D, Becka M, Voith B et Despite advances over the years,
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
most currently available anticoagu-
SM. New anticoagulants. J Thromb Haemost. 2005; 3:1843–53. 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

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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 ize how the drug may be used safely dic surgery.24-26 Dabigatran was com-
patients requiring non-heparin an- in patients with various levels of re- pared with s.c. enoxaparin in three
ticoagulant therapies, as an alterna- nal impairment. randomized double-blind studies,
tive to the synthetic pentasaccharide In contrast to dabigatran, the two of which looked at VTE preven-
fondaparinux. bioavailability of apixaban and ri- tion in patients undergoing total
The times to peak plasma con- varoxaban is greater than 50% and knee replacement surgery (known as
centration and half-lives of the three 80%, respectively.17,18,23 Renal elimi- RE-MOBILIZE and RE-MODEL),
emerging oral anticoagulants dab- nation is higher for rivaroxaban while the third study, known as
igatran, rivaroxaban, and apixaban (66%) than for apixaban (25%), but RE-NOVATE, was conducted in pa-
are similar. Their half-lives facilitate the 66% for rivaroxaban includes an tients undergoing total hip replace-
administration once or twice daily. inactive metabolite. Approximately ment surgery (Table 2).24-26 The same
The bioavailability of dabigatran is 30% of the parent drug is cleared primary efficacy outcome (total VTE
low, requiring the administration of by the kidneys in patients taking events and all-cause mortality) was
large doses to achieve therapeutic rivaroxaban. 6 Nevertheless, renal used in all three studies, but the bleed-
concentrations. In addition, dab- impairment may be a consideration ing definitions used in the safety anal-
igatran is administered as a prodrug, in the dosing of rivaroxaban. Apixa- ysis varied somewhat. The same two
dabigatran etexilate, that requires an ban is less likely than rivaroxaban dabigatran dosages (150 mg or 220
acidic environment for absorption.18 to accumulate in patients with renal mg twice daily) were used in all three
Therefore, clinically relevant interac- impairment. Although use in pa- studies, although a half dose was used
tions with proton pump inhibitors tients with renal impairment may as the initial dose in RE-NOVATE.
and other acid-suppressing therapies be of less concern with apixaban The timing of the first dose was 1-4
are likely for dabigatran.19 However, and rivaroxaban, both agents are hours after surgery in two studies
the risk for drug interactions with metabolized by cytochrome P-450 (RE-MODEL and RE-NOVATE)
dabigatran is low compared with 3A4.18 These drugs can interact with and 6-12 hours after surgery in the
the other emerging agents because potent inhibitors of both CYP3A4 other study. The duration of therapy
cytochrome P-450 enzymes are not and P-glycoprotein, and their use was shorter in the RE-MODEL and
involved in metabolism of the drug.22 will likely require a level of vigilance RE-MOBILIZE studies of knee
Since dabigatran is eliminated pri- for potential drug interactions simi- replacement patients than in
marily by the kidneys, dosage reduc- lar to that for warfarin. RE-NOVATE (i.e., hip replacement
tion may be required for patients Dabigatran efficacy and safety. patients), but this difference is
with renal impairment.22 Drug accu- The efficacy and safety of dabigatran appropriate given the current
mulation is a concern because of the for VTE prevention was explored guideline-based recommendations
potential for bleeding, and further in three key clinical trials involving for duration of VTE prophylaxis
research is needed to fully character- patients undergoing major orthope- 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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The enoxaparin dosing regimen tween enoxaparin and either dose of of minor bleeding were not report-
commonly used in North America dabigatran. ed). Thus, on the basis of the current
(30 mg twice daily) was used in RE- Despite these positive results in results, dabigatran appears to be a
MOBILIZE, but the less intense evaluating the potential benefit of potentially useful option for VTE
regimen preferred in Europe (40 dabigatran in VTE prevention, it is prevention but may be less effective
mg once daily) was used in the most instructive to look at the two than more aggressive regimens of the
other two studies. These differences studies involving knee replacement LMWH enoxaparin.
in dosing are important to consider patients (Table 2). In RE-MODEL, Despite the varied results in VTE
because they may have affected the both the 150 mg and 220 mg once prevention, the dabigatran clinical
study results and may have different daily dose of dabigitran met the non- trial program is a promising one and
implications for clinical practice in inferiority criteria with enoxaparin includes other studies of the drug for
different regions of the world. 40 mg once daily. In RE-MOBILIZE use in VTE treatment, for thrombo-
In RE-NOVATE (i.e., total hip (i.e., total knee replacement surgery sis prevention in patients with atrial
replacement surgery patients receiv- patients receiving the North Ameri- fibrillation, and in conjunction with
ing the European enoxaparin dosing can enoxaparin dosing regimen), antiplatelet therapy for the treatment
regimen), the primary efficacy out- dabigatran was judged inferior to acute coronary syndrome (ACS).27,28
come (i.e., composite of total VTE enoxaparin (i.e., non-inferiority cri- In patients with atrial fibrillation,
events and all cause mortality) had teria were not met).24 The incidence dabigatran 150 mg twice daily was
occurred after 28–35 days in 53 of the primary outcome after 12–15 associated with lower rates of stroke
(6.0%) of 880 patients in the dabiga- days of treatment was 31% with dab- and systemic embolism and similar
tran 220 mg/day group, 75 (8.6%) of igatran 220 mg/day (p = 0.02 versus rates of major hemorrhage com-
874 patients in the dabigatran 150 enoxaparin), 34% with dabigatran pared with warfarin.28 In addition, in
mg/day group, and 60 (6.7%) of 897 110 mg/day (p < 0.001 versus enox- patients with acute VTE, dabigatran
patients in the enoxaparin group. aparin), and 25% with enoxaparin. 150 mg twice daily was as effective
Both dabigatran doses were judged Potential explanations for the lack as warfarin in preventing VTE recur-
non-inferior to enoxaparin.26 There of positive findings for dabigatran rence, with a similar incidence of
were no significant differences in include the use of a more intense bleeding.27
the incidence of major bleeding be- enoxaparin dosing regimen com- Apixaban efficacy and safety.
tween enoxaparin (1.6%) and either pared with that used in RE-NOVATE The efficacy and safety of apixaban
dose of dabigatran (2.0%, p = 0.44 as well as a lower initial dose of dab- 2.5 mg twice daily and enoxaparin
for 220 mg/day; 1.3% p = 0.60 for igatran. The rates of major bleeding for VTE prevention in patients un-
150 mg/day). Similarly, the rates of and clinically relevant non-major dergoing major orthopedic surgery
clinically relevant non-major and bleeding were similar with both dab- were compared in three random-
minor bleeding did not differ be- igatran doses and enoxaparin (rates 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- major bleeding (3.5% versus 4.8%, duration of enoxaparin therapy
sults have been reported only for respectively, p = 0.09). was used in RECORD 1 (35 days)
ADVANCE-1 and ADVANCE-2. As with dabigatran, the results of than in RECORD 2 (14 days).31,32
Similar to dabigatran, the apixaban apixaban clinical trials in patients Rivaroxaban was judged superior to
clinical trial program also includes undergoing major orthopedic sur- enoxaparin in RECORD 1 because
studies of use of the drug for VTE gery depended on the enoxaparin the incidence of the primary out-
treatment, stroke prevention in dosing regimen used. Although come after 35 days of treatment was
patients with atrial fibrillation, and underlying issues with statistical significantly lower in the rivaroxaban
treatment of ACS in conjunction power and methodology were likely group (1.1%) than in the enoxaparin
with antiplatelet therapy. in play, the results were less favorable group (3.7%, p < 0.001).31 There was
ADVANCE-1 involved 3195 pa- with the more aggressive regimen of no significant difference between
tients undergoing total knee replace- enoxaparin 30 mg twice daily than rivaroxaban and enoxaparin in the
ment and compared apixaban with with the 40 mg once-daily regimen. incidence of major bleeding (0.3%
enoxaparin 30 mg s.c. twice daily Additional studies comparing the versus 0.1%, respectively, p = 0.18).
beginning 12–24 hours after surgery efficacy of apixaban with the North The results of RECORD 2 are consis-
and continued for 10–14 days.29 The American enoxaparin regimen are tent with these findings.
primary efficacy outcome was total needed. Rivaroxaban was judged superior
VTE events, and the criteria for non- Rivaroxaban efficacy and safety. to enoxaparin in the two clinical
inferiority included an upper limit The efficacy and safety of rivaroxa- studies of patients undergoing knee
of the 95% confidence interval of ban for preventing VTE in patients replacement surgery.33,34 The results
1.25). After 10–14 days of treatment, undergoing major orthopedic sur- of RECORD 4 provide greater in-
the primary efficacy outcome oc- gery have been evaluated in four sight for American clinicians than
curred in 9.0% of apixaban-treated randomized, double-blind clinical the results of RECORD 3 because the
patients and 8.8% of enoxaparin- trials.31-34 The rivaroxaban clinical North American enoxaparin dos-
treated patients (p = 0.06, relative trial program also includes studies ing regimen was used in RECORD
risk, 1.02; 95% confidence interval, of the drug for VTE treatment, VTE 4 and the European enoxaparin
0.78 to 1.32). Since the upper bound- prevention in medically ill patients, regimen was used in RECORD 3.
ary of the 95% confidence interval thrombosis prevention in patients In RECORD 4, the primary efficacy
exceeded 1.25, apixaban did not with atrial fibrillation, and treat- outcome occurred in significantly
meet the criteria for non-inferiority ment of ACS in conjunction with fewer rivaroxaban-treated patients
to enoxaparin. Although the trial antiplatelet therapy. Results of the (6.9%) than enoxaparin-treated
did enroll a sufficient number of Einstein-Extension Study of ex- patients (10.1%, p = 0.0118) after
patients based on the prespecified tended rivaroxaban therapy for 6–12 14 days of treatment.34 There was
power analysis, the overall event rate months in patients with established no significant difference between
was much lower than anticipated and VTE were recently reported.35 The rivaroxaban and enoxaparin in the
likely influenced the statistical analy- drug was effective for preventing incidence of major bleeding (0.7%
sis. The incidence of major bleeding VTE recurrence, with a low risk for versus 0.3%, respectively, p = 0.1096).
and clinically relevant non-major major bleeding. Similarly, no significant difference
bleeding was significantly lower with Two of the rivaroxaban studies between treatments in major bleed-
apixaban (2.9%) than with enox- in patients undergoing major or- ing rates was observed in RECORD
aparin (4.3%, p = 0.03). thopedic surgery involved total hip 3 (p = 0.93).
ADVANCE-2 involved 3057 pa- replacement surgery, and the other Desirudin efficacy and safety.
tients undergoing total knee replace- two studies involved knee replace- The efficacy and safety of desiru-
ment, and the comparison was made ment surgery (Table 3).31-34 The same din for preventing VTE in patients
between apixaban and enoxaparin 40 rivaroxaban dosage (10 mg once undergoing hip replacement surgery
mg s.c. once daily beginning 12 hours daily) and primary endpoint (total has been established for over a de-
before surgery.30 After 12 days, the VTE or death) were used in all four cade. Two randomized, multicenter,
incidence of total VTE events was studies, but the duration of therapy placebo-controlled trials compared
significantly lower with apixaban and enoxaparin dosage varied. In desirudin at a dose of 15 mg s.c. twice
(15.1%) than enoxaparin (24.4%, the studies of total hip replace- daily with either UFH 5000 units
p < 0.001). There was no significant ment (known as RECORD 1 and three times daily 36 or enoxaparin
difference between apixaban and RECORD 2), the European enox- 40 mg s.c. once daily.37 In the lat-
enoxaparin in the incidence of major aparin dosing regimen was used, ter, desirudin was given 30 minutes
bleeding and clinically relevant non- but a longer and more appropriate prior to surgery after the induction

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SYMPOSIUM  Emerging anticoagulants

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

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SYMPOSIUM  Emerging anticoagulants

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plete response letter for rivaroxaban. 2009; 361:1139-51. webprog r am/Pap er25669.ht ml
http://www.jnj.com/connect/news/ 29. Lassen MR, Raskob GE, Gallus A et al. (accessed 2009 Dec 16).
all/20090528_103000 (accessed 2009 Dec Apixaban or enoxaparin for thrombopro- 36. Eriksson BI, Ekman S, Basel L et al. Pre-
15). phylaxis after knee replacement. N Engl J vention of thromboembolism with use of
22. Stangier J. Clinical pharmacokinetics and Med. 2009; 361:594-604. recombinant hirudin. J Bone Joint Surg.
pharmacodynamics of the oral direct 30. Lassen MR, Gallus AS, Pineo GF et al. 1997; 79-A:326-33.
thrombin inhibitor dabigatran etexilate. Apixiban versus enoxaparin for throm- 37. Eriksson BI, Wille-Jorgensen P, Kalebo P
Clin Pharmacokinet. 2008; 47:285-95. boprophylaxis after knee replacement et al. A comparison of recombinant hiru-
23. Borris LC. New compounds in the man- (ADVANCE -2): a randomized double- din with a low-molecular weight heparin
agement of venous thromboembolism blind trial. Lancet 2010; 375: 807-15. to prevent thromboembolic complica-
after orthopedic surgery: focus on rivar- 31. Eriksson BI, Borris LC, Friedman RJ et tions after total hip replacement. N Engl J
oxaban. Vasc Health Risk Manag. 2008; al. Rivaroxaban versus enoxaparin for Med. 1997; 337:1329-35.
4:855-62. thromboprophylaxis after hip arthro- 38. Desirudin package insert. Hunt Valley,
24. Ginsberg JS, Davidson BL, Comp PC et plasty. N Engl J Med. 2008; 358:2765- MD: Canyon Pharmaceuticals; 2010
al. Oral thrombin inhibitor dabigatran 75. Jan.
etexilate vs North American enoxaparin 32. Kakkar AK, Brenner B, Dahl OE et al. Ex- 39. Stangier J. Clinical pharmacokinetics and
regimen for prevention of venous throm- tended duration rivaroxaban versus short- pharmacodynamics of the oral direct
boembolism after knee arthroplasty sur- term enoxaparin for the prevention of thrombin inhibitor dabigatran etexilate.
gery. J Arthroplasty. 2009; 24:1-9. venous thromboembolism after total hip Clin Pharmacokinet. 2008; 47(5):285-
25. Eriksson BI, Dahl OE, Rosencher N et arthroplasty: a double-blind, randomised 295.
al. Oral dabigatran etexilate vs. subcu- controlled trial. Lancet. 2008; 372:31-9. 40. Mueck W, Borris LC, Dahl OE et al.
taneous enoxaparin for the prevention 33. Lassen MR, Ageno W, Borris LC et al for Population pharmacokinetics and phar-
of venous thromboembolism after total the RECORD3 investigators. Rivaroxaban macodynamics of once and twice daily
knee replacement: the RE-MODEL ran- versus enoxaparin for thromboprophy- rivaroxaban for the prevention of venous
domized trial. J Thromb Haemost. 2007; laxis after total knee arthroplasty. N Engl J thromboembolism in patients undergo-
5:2178-85. Med. 2008; 358:2776-86. ing total hip replacement. Thromb Hae-
26. Eriksson BI, Dahl OE, Rosencher N et al. 34. Turpie AG, Lassen MR, Davidson BL et most. 2008; 100:453-461.
Dabigatran etexilate versus enoxaparin al for the RECORD4 investigators. Rivar-

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

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

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SYMPOSIUM  Clinical and management challenges

Larger-than-usual doses of UFH and higher incidence of VTE compared In the PRINCE trial, a fixed UFH
LMWH, with weight-based dosing of with patients who received enox- dosage of 5000 units s.c. every eight
LMWH, are recommended by ACCP aparin 30 mg s.c. every 12 hours for hours was used in medically ill pa-
for these patients.2 However, the 10 days.4 Fondaparinux 2.5 mg s.c. tients, and approximately one third
ACCP guidelines do not provide de- once daily is recommended by ACCP of the patients were overweight. We
tailed guidance for choosing among for VTE prevention in nonobese have no evidence to support our
and dosing these anticoagulants in patients undergoing orthopedic or approach to UFH dosing in medi-
obese patients like Mr. Vegas who other major surgery, and the drug cally ill patients who are obese,
undergo bariatric surgery. Mr. Vegas may have a therapeutic effect on however.
has a body mass index (BMI) of 58 subclinical thrombosis that develops I might dose warfarin empirically,
kg/m2, making him morbidly obese during or after surgery.1 However, titrating to an international nor-
(a BMI >40 kg/m2 often is used to the appropriate dose to use for obese malized ratio (INR) of 2.0 to 3.0 as
define morbid obesity). What anti- patients undergoing bariatric sur- recommended by ACCP, rather than
coagulant therapy would you use to gery is unclear. Weight-based dos- using the 2006 dose.1 This approach
prevent VTE after bariatric surgery ing is used for VTE treatment, with eliminates body weight as a consider-
in Mr. Vegas? fixed daily 10-mg doses for patients ation in dosing.
Dr. Dager: It would be important weighing more than 100 kg. A daily Dr. Haines: Would you consider
to ascertain whether Mr. Vegas’s 5-mg dose might be considered for using the activated partial throm-
DVT in 2006 was idiopathic or pro- VTE prophylaxis in Mr. Vegas, al- boplastin time (aPTT) to guide
voked as the result of a precipitating though there is no evidence to sup- UFH dosing (e.g., a target aPTT of
factor, such as a long airplane flight port its use. This dose may be larger 40 seconds)? There is no evidence
or a surgical procedure. Neverthe- than is required. to support this approach, but using
less, Mr. Vegas is at higher risk for An aggressive unfractionated hep- aPTT to guide therapy would at least
VTE than other patients undergo- arin (UFH) regimen of 7500  units demonstrate that an anticoagulant
ing bariatric surgery because of his s.c. every eight hours might be effect has been achieved.
obesity and history of DVT. My considered for Mr. Vegas, although Dr. Dager: At UC Davis Medical
biggest concern is the increased risk evidence to support this regimen also Center, we might use aPTT values
for pulmonary embolism because of is lacking. When making the transi- to guide UFH dosing for VTE pro-
his obesity. tion to warfarin therapy, a factor to phylaxis in patients with advanced
An effort to improve the diet and consider in choosing a warfarin dose age (e.g., 80 years or older) or a
lose weight prior to bariatric surgery is the likelihood that Mr. Vegas may low body weight (e.g., <50 kg). We
usually is recommended for patients respond differently than he did three would check the aPTT periodically
like Mr. Vegas. Enoxaparin 40 mg years ago. Therefore, use of the same to ensure that anticoagulation is not
subcutaneously (s.c.) every 12 hours dose of warfarin that he received in excessive in these patients.
has been used successfully to prevent 2006 may not be optimal. We have noticed that patients with
VTE in patients undergoing bariat- Dr. Trujillo: I concur with multiple acute traumas often are
ric surgery for morbid obesity.3 We Dr. Dager. I would use enoxaparin antithrombin deficient during the
perform a lot of bariatric surgery at 40 mg s.c. every 12 hours because of first few days after hospital admission,
the University of California (UC) the available evidence of its safety which we have linked to increased
Davis Medical Center. As improved and efficacy for VTE prevention after incidence of VTE and mortality in
surgical techniques have led to bariatric surgery in the morbidly critically ill trauma patients.6 We use
shorter lengths of stay and shorter obese patient population.3 UFH infusions with a target aPTT of
durations of VTE prophylaxis, we Whether an aggressive UFH 35-45 seconds in trauma patients. We
subsequently observed an increase in dosing regimen is reasonable for have observed low DVT rates with
the incidence of VTE. Therefore, we Mr. Vegas is unclear. At the University this approach, although it is not sup-
extended our dosing of enoxaparin of Colorado Hospital, we often have ported by clinical trial data.
to 40 mg s.c. every 12 hours starting difficulty determining the proper In young pediatric patients, you
preoperatively, and prophylaxis is dosage of UFH to use for VTE pro- might consider the possibility of the
continued for at least seven days after phylaxis in medically ill patients who presence of a hypercoagulable state
bariatric surgery. To date, we have are obese. We typically use a dosage due a hereditary deficiency in en-
not observed any VTE complications, based on weight extrapolated from dogenous anticoagulants.1 This pos-
which is consistent with a report in the Thromboembolism-Prevention sibility might need to be taken into
which bariatric surgery patients who in Cardiac or Respiratory Disease consideration in making decisions
received 3 days of prophylaxis had a With Enoxaparin (PRINCE) trial.5 about anticoagulant use or dosing

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SYMPOSIUM  Clinical and management challenges

to prevent VTE in an obese pediatric failure (CHF). During a previous has not yet been formally studied.
patient. admission one month ago for CHF Moreover, clinical trials using these
exacerbation, he was given UFH new drugs for VTE prophylaxis in
Clinical challenge 2 5000 units s.c. every eight hours for medically ill patients like Mr. Genoa
Dr. Haines: Mrs. Carson is a 63- VTE prophylaxis. His platelet count have not yet been published.
year-old woman who is admitted for had dropped from 260,000/µL to I would probably use fonda-
abdominal surgery for colon cancer. 130,000/µL at the time of discharge, parinux in Mr. Genoa, although I
She weighs 156 lb (71 kg). An epi- but no diagnostic testing for heparin- would be concerned about the pos-
dural catheter was placed for pain induced thrombocytopenia (HIT) sibility that his CHF is severe enough
control, but the surgeon would like was performed. What is the best to cause significant renal impairment.
to remove it today (postoperative choice for anticoagulant therapy to The elimination of fondaparinux is
day 1). Mrs. Carson has been receiv- prevent VTE in Mr. Genoa now? prolonged and the risk for bleeding
ing dalteparin 5000 units s.c. daily for Dr. Dager: The UFH therapy is increased in patients with renal
VTE prophylaxis since she is at high and 50% reduction in platelet count impairment.8 The drug is contrain-
risk because of her cancer and sur- during the previous hospitalization dicated in patients with severe renal
gery.1 Spinal hematoma formation suggests that HIT might have devel- impairment (creatinine clearance
with long-term or permanent paraly- oped in Mr. Genoa, which increases <30 mL/min). Therefore, I would
sis is a rare complication of the use of his risk for thromboembolism. The check Mr. Genoa’s renal function be-
epidural catheters in anticoagulated platelet count should be checked. fore initiating fondaparinux. I might
patients.1 Insertion and removal of The timing of suspected HIT only use a longer dosing interval (e.g., 48
epidural catheters in patients receiv- one month ago creates a potential hours) for Mr. Genoa, instead of the
ing anticoagulants increases the risk risk for rapid-onset HIT if UFH or customary 24-hour interval, if renal
of this complication. When is the LMWH is used now. Circulating dysfunction is present and no other
best time to remove the catheter HIT antibodies formed during the reasonable options exist.
from Mrs. Carson in relation to her initial exposure to heparin will react
dalteparin therapy? if heparin is administered within Clinical challenge 4
Dr. Trujillo: The timing of cath- 100 days (especially within 30 days).6 Dr. Haines: Mrs. Minden is a
eter removal in Mrs. Carson is a The HIT antibodies formed during 73-year-old woman who had hip
dilemma because of the need to UFH therapy often cross-react with replacement surgery four days ago.
remove the catheter at a time when LMWH, eliminating this class of Fondaparinux 2.5 mg s.c. once daily
the plasma concentration and thera- agents as an option.7 Except for rare was started eight hours after surgery
peutic effect of dalteparin are low. circumstances, fondaparinux does for VTE prophylaxis. Mrs. Minden
This is best done late in the dosing not cross-react with HIT antibod- will be discharged to a rehabilitation
interval but well before the next dose. ies, so this drug may be one option facility today. For how long should
The dosing interval in Mrs. Carson is for VTE prophylaxis in patients like fondaparinux be continued?
24 hours, so catheter removal could Mr. Genoa with strongly suspected Dr. Dager: The ACCP guidelines
be recommended at least 12 hours or confirmed HIT.7 Warfarin alone recommend extended prophylaxis
after a dose and 6 hours before the is not recommended for Mr. Genoa for up to 35 days using LMWH, a vi-
next dose. if his platelet count is low because it tamin K antagonist, or fondaparinux
Dr. Dager: The strategy suggested could increase the risk for thrombosis after total hip or knee replacement.1 I
by Dr. Trujillo is reasonable. Another and result in venous limb gangrene.7 recommend a longer duration (e.g.,
approach to epidural catheter removal Dr. Trujillo: I ag re e w ith six weeks) of VTE prophylaxis after
in Mrs. Carson is to schedule it 22 Dr.  Dager that it is important to hip replacement surgery for patients
hours after a dalteparin dose, which check Mr.  Genoa’s platelet count like Mrs. Minden because VTE usu-
will be 2 hours before the next dose. now. The 260,000/µL or 130,000/µL ally occurs later in this patient popu-
There is no one best approach. Clini- value measured one month ago could lation than in patients undergoing
cal judgment should be used, and have been a laboratory error. total knee replacement surgery.9 She
institutional scheduling and staffing If the oral direct thrombin (fac- could switch to warfarin and stop
issues need to be considered. tor IIa) inhibitor dabigatran or oral fondaparinux once an INR of 2.0 to
direct factor Xa inhibitor apixaban 3.0 is achieved, which is the range
Clinical challenge 3 or rivaroxaban were available, I recommended by ACCP and con-
Dr. Haines: Mr. Genoa is a 58- might consider using one of them. In sistent with most published studies
year-old man who is admitted for theory, these agents should not cross- of patients undergoing hip or knee
exacerbation of congestive heart react with HIT antibodies, but this replacement.1

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SYMPOSIUM  Clinical and management challenges

Dr. Haines: I commonly see in- inhibitor dabigatran and the direct therapeutic failure of less expensive
jectable anticoagulants discontinued factor Xa inhibitors apixaban and agents?
when the INR exceeds 1.5 during rivaroxaban are administered orally Dr. Trujillo: Decisions about add-
concomitant warfarin therapy for once or twice daily. These oral agents ing new anticoagulants to the formu-
VTE prophylaxis, an approach that have a rapid onset of action, which lary depend on formulary openness,
is not consistent with evidence-based circumvents the need for bridge P&T committee dynamics, and in-
clinical practice guidelines. Studies therapy while waiting for a therapeu- stitutional characteristics and needs.
comparing the use of various INRs tic INR to be achieved before discon- The introduction of new antico-
for this transition have not been tinuing injectable anticoagulation agulants will pose a dilemma to P&T
conducted. I’m not sure how com- when warfarin is initiated for VTE committees. I would not restrict the
fortable we should be with the use of treatment. use of new anticoagulants to cases of
lower INRs. Greater ease of use may be an therapeutic failure of established
Dr. Dager: I question the ad- advantage of newer anticoagulants agents, but I would restrict the pre-
equacy of using the lower INR target over older agents. Their availability scribing to specific physician groups
ranges (e.g., 1.5 to 2.0) for the transi- may promote practitioner adher- and indications to avoid widespread
tion to warfarin alone, as done by ence to VTE prophylaxis guidelines, use in patient populations in which
some clinicians, although 1.5 to 3.0 increase patient adherence to thera- the drug may not yet have been
was evaluated in one comparative py, and ultimately lead to improved found safe and effective.
study of patients undergoing hip or effectiveness and outcomes. The Dabigatran might be added to the
knee replacement.10 Of the other 14 weight given to each consideration formulary for both stroke prevention
comparative clinical trials in knee or will vary among health systems, in patients with atrial fibrillation and
hip surgery, the lowest INR target was depending on their institutional VTE prevention in patients undergo-
1.8 and the highest was 3.0. I think a priorities and culture. Performance ing major orthopedic surgery. Safety
compromise approach, with a target and outcomes reporting and pay- and efficacy data are available for use
INR of at least 1.8 and a maximum for-performance requirements per- of the drug in this surgical popula-
of 3.0, could be considered. taining to anticoagulant use for VTE tion, although the efficacy data are
prevention may influence formulary mixed.15-17
Management challenge 1 decisions involving new anticoagu- Published data are not yet avail-
Dr. Haines: The pharmacy and lants at Virginia City Hospital and able for the use of apixaban for stroke
therapeutics (P&T) committee at other institutions. prevention in patients with atrial
Virginia City Hospital is evaluat- fibrillation. Therefore, its use should
ing several new anticoagulants— Management challenge 2 be limited to VTE prevention in pa-
apixaban, dabigatran, idraparinux, Dr. Haines: Dr. Henderson, a car- tients undergoing major orthopedic
and rivaroxaban—for addition to diologist at Virginia City Hospital, surgery if the drug is added to the
the formulary. What considerations has requested the addition of dab- formulary.
should enter into the deliberations igatran to the formulary for stroke While not formally requested,
and formulary decisions? prevention in patients with atrial rivaroxaban should be considered
Dr. Trujillo: The safety, effective- fibrillation. The drug has been asso- in conjunction with the requests by
ness, ease of use, and cost of the new ciated with lower rates of stroke and Drs. Henderson and Reno at Virginia
agents compared with older agents systemic embolism and similar rates City Hospital as part of a compre-
already on the formulary are pri- of major hemorrhage compared hensive review of the entire class of
mary concerns. Cost analyses should with warfarin in this patient popu- medications. Published safety and
take into consideration the costs of lation.12 Dr. Reno, an orthopedic efficacy data are available for the use
managing adverse effects, particu- surgeon at the same institution, has of rivaroxaban for VTE prevention in
larly bleeding and thromboembolic requested the addition of apixaban patients undergoing major orthope-
events. to the formulary for VTE prevention dic surgery.18-21 The formulary status
An oral route of administration on the basis of limited safety and of new anticoagulants should be
and infrequent dosing are associated efficacy data in patients undergoing re-evaluated as additional safety and
with ease of use. Idrabiotaparinux is major orthopedic surgery.13,14 What efficacy data become available.
a biotinylated form of the indirect formulary additions should be made
factor Xa inhibitor idraparinux with at this institution at this time? The Conclusion
a long half-life that permits weekly acquisition costs of the drugs prob- Certain patients at risk for VTE
administration.11 It is given by s.c. ably will be high. Should use of the can present a clinical challenge. The
injection. The oral direct thrombin new agents be restricted to cases of introduction of new anticoagulants

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SYMPOSIUM  Clinical and management challenges

may pose a management challenge bolic complications. J Trauma. 1996; mostasis XXII Congress, Boston, MA:
41:396-405 July 13, 2009.
in determining whether to add the 7. Warkentin TE, Greinacher A, Koster 15. Ginsberg JS, Davidson BL, Comp PC et
agents to the formulary and restrict A et al. Treatment and prevention of al. Oral thrombin inhibitor dabigatran
their use. The availability of new anti- heparin-induced thrombocytopenia. etexilate vs North American enoxaparin
American College of Chest Physicians regimen for prevention of venous
coagulants may help overcome some evidence-based clinical practice guide- thromboembolism after knee arthro-
clinical challenges in preventing VTE lines (8th edition). Chest. 2008; 133(6 plasty surgery. J Arthroplasty. 2009; 24:
and improve patient outcomes. Suppl):340S-80S. 1-9.
8. Arixtra package insert. Research Triangle 16. Eriksson BI, Dahl OE, Rosencher N et
References Park, NC: GlaxoSmithKline; 2009 Oct. al. Oral dabigatran etexilate vs. subcu-
1. Geerts WH, Bergqvist D, Pineo GF et al. 9. White RH, Romano PS, Zhou H et al. taneous enoxaparin for the prevention
Prevention of venous thromboembo- Incidence and time course of throm- of venous thromboembolism after total
lism: American College of Chest Physi- boembolic outcomes following total hip knee replacement: the RE-MODEL ran-
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133(6 Suppl):381S-453S. 10. RD Heparin Arthroplasty Group. RD 17. Eriksson BI, Dahl OE, Rosencher N et al.
2. Hirsh J, Bauer KA, Donati MB et al. Par- heparin compared with warfarin for Dabigatran etexilate versus enoxaparin
enteral anticoagulants: American Col- prevention of venous thromboembolic for prevention of venous thromboem-
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A comparison of two different prophy- ticoagulant effects of idraparinux after al. Rivaroxaban versus enoxaparin for
lactic dose regimens of low molecular termination of therapy for prevention thromboprophylaxis after hip arthro-
weight heparin in bariatric surgery. Obes of recurrent venous thromboembolism: plasty. N Engl J Med. 2008; 358:2765-
Surg. 2002; 12:19-24. observations from the van Gogh trials. 75.
4. Raftopoulos I, Martindale C, Cronin Eur J Clin Pharmacol. 2008; 64:555-63. 19. Kakkar AK, Brenner B, Dahl OE et al.
A et al. The effect of extended post- 12. Connolly SJ, Ezekowitz MD, Yusuf S Extended duration rivaroxaban versus
discharge chemical thromboprophylax- et al. Dabigatran versus warfarin in short-term enoxaparin for the preven-
is on venous thromboembolism rates patients with atrial fibrillation. N Engl J tion of venous thromboembolism after
after bariatric surgery: a prospective Med. 2009; 361:1139-51. total hip arthroplasty: a double-blind,
comparison trial. Surg Endosc. 2008; 13. Lassen MR, Raskob GE, Gallus A et al. randomised controlled trial. Lancet.
22:2384-91. Apixaban or enoxaparin for thrombo- 2008; 372:31-9.
5. Kleber FX, Witt C, Vogel G et al. Ran- prophylaxis after knee replacement. N 20. Lassen MR, Ageno W, Borris LC et al.
domized comparison of enoxaparin Engl J Med. 2009; 361:594-604. for the RECORD3 investigators. Rivar-
with unfractionated heparin for the 14. Lassen MR, Gallus AS, Pineo GF et oxaban versus enoxaparin for thrombo-
prevention of venous thromboembolism al. Late breaking clinical trial: the prophylaxis after total knee arthroplasty.
in medical patients with heart failure or ADVANCE-2 study: a randomized dou- N Engl J Med. 2008; 358:2776-86.
severe respiratory disease. Am Heart J. ble-blind trial comparing apixaban with 21. Turpie AG, Lassen MR, Davidson BL
2003; 145: 614-21. enoxaparin for thromboprophylaxis et al. for the RECORD4 investigators.
6. Owings JT, Bagley M, Gosselin R et al. after total knee replacement. J Thromb Rivaroxaban versus enoxaparin for
Effect of critical injury on plasma an- Haemost. 2009;7(Suppl 2):abstract thromboprophylaxis after total knee
tithrombin activity: low antithrombin LB-MO-005. Presented at the Interna- arthroplasty (RECORD4): a randomised
levels are associated with thromboem- tional Society on Thrombosis and Hae- trial. Lancet. 2009; 373:1673-80.

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5b-Advantage_10-0179.indd 30 4/28/2010 3:15:42 PM


Continuing Education

Continuing Education

Improving anticoagulant use after total hip or knee replacement


surgery?

for prevention of venous a. Evidence-based guidelines.


b. Hospital/physician quality

thromboembolism measures.
c. Mandatory practice and out-
Article #204-000-10-429-H01P comes reporting.
Knowledge-based activity d. Pay-for-performance
Qualifies for 2.5 hours (0.25 CEU) of continuing-education credit
requirements.
Learning objectives Self-assessment questions 5. Which of the following should
After studying these articles, the reader For each question there is only one best health-system pharmacists avoid in
should be able to answer. order to improve the quality of care
and address the needs of patients at
1. Describe the risk factors for venous 1. Which of the following components
risk for VTE?
thromboembolism (VTE). of Virchow’s triad does factor V
Leiden reflect? a. Group decision making.
2. Explain the evolution of quality b. Multidisciplinary input.
improvement efforts as they pertain a. A hypercoagulable state alone.
c. Autonomous problem solving.
to VTE prevention. b. Endothelial injury alone.
d. Teamwork.
3. Describe strategies that health-system c. Circulatory stasis alone.
d. Endothelial injury and circula- 6. Which of the following is a com-
pharmacists can use to close the mon reason for failure to adhere to
cultural gap between 20th- and tory stasis.
clinical practice guidelines for VTE
21st-century medicine and improve 2. Which of the following is a risk
prophylaxis?
anticoagulant use and outcomes in factor for venous thromboembo-
patients at risk for VTE. lism (VTE) commonly found in a. Excessive reliance on hema-
hospitalized patients? tologists to perform the risk
4. Identify a cause of difficulty in ­assessing ­assessment.
and reducing VTE risk, and  recom- a. Diabetes mellitus.
b. Excessive reliance on clinical
mend a strategy for the use of drug b. Hyperlipidemia.
practice guidelines.
therapy for VTE prophylaxis in a pa- c. Peptic ulcer disease.
c. A lack of standardized methods
tient with unique characteristics that d. Prolonged immobility.
for measuring and defining
require special consideration. 3. Which of the following is the most clinical trial outcomes.
5. Discuss the shortcomings of cur- important and therefore must d. A lack of awareness of the
rently available anticoagulants and occur first in the quality-of-care ­impact of VTE on morbidity
the characteristics of the ideal an- ­continuum? and mortality.
ticoagulant, and compare and con- a. Clinical studies. 7. There is a lack of consensus among
trast the mechanisms of action, b. Evidence-based guidelines. health care practitioners and
pharmacokinetics, administration, c. Mandatory practice and out- controversy surrounds use of which
efficacy, safety, and potential for drug comes reporting. of the following drug therapies for
interactions from currently available d. Pay-for-performance VTE prophylaxis?
and emerging anticoagulants for VTE requirements.
prevention. a. Aspirin.
4. Which of the following parts of b. Low molecular weight heparin
6. Explain a clinical or management chal- the quality-of-care continuum (LMWH).
lenge associated with VTE ­prevention, is represented by “never event” c. Unfractionated heparin (UFH).
and outline a practical approach to reimbursement policies estab- d. Warfarin.
overcoming the challenge. lished by the Centers for Medicare
and Medicaid Services for VTE

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Continuing Education

8. Which of the following durations of c. It is routinely recommended b. Differences in the duration


VTE prophylaxis is recommended only for patients with severe of treatment and enoxaparin
after total hip replacement surgery? renal impairment. ­dosing regimen used.
a. 1 week. d. It is not routinely recommended c. Differences in the duration of
b. 6 weeks. for any patients. treatment and comparator used.
c. 10 weeks. 12. Which of the following is a char- d. The results of clinical trials
d. 6 months. acteristic of the ideal anticoagulant should never be compared.
9. Which of the following enoxaparin for VTE prevention? 17. Which of the following statements
dosage adjustments should be made a. Narrow therapeutic index. best characterizes the results of
for patients with morbid obesity b. Irreversible action. ­clinical trials of rivaroxaban for
undergoing knee replacement c. Oral route of administration. VTE prevention in patients under-
surgery? d. Available in a single dosage going major orthopedic surgery?
a. The dosage should be decreased strength. a. The drug was superior in effi-
to 20 mg every 24 hours. 13. Which of the following is a new oral cacy to enoxaparin but increased
b. The dosage should be decreased vitamin K antagonist that is not the risk for major bleeding.
to 30 mg every 24 hours. metabolized by cytochrome P-450 b. The drug was superior in
c. The dosage should be increased enzymes? ­efficacy to enoxaparin without
to 40 mg every 12 hours. increasing the risk for major
a. Apixaban.
d. The dosage should be increased bleeding.
b. Dabigatran etexilate.
to 50 mg every 12 hours. c. The drug was not inferior in
c. Rivaroxaban.
­efficacy to enoxaparin and was
10. For which of the following issues is d. Tecarfarin.
not associated with an increased
consensus lacking among clinicians 14. Which of the following is an the risk for major bleeding.
in the prevention of VTE? ­emerging oral anticoagulant that d. The drug was inferior to
a. The need to maintain the INR might interact with proton pump ­enoxaparin in terms of efficacy
during warfarin therapy between inhibitors and other drugs that and safety.
2 and 3. lower gastric pH?
18. Which of the following best
b. The need to avoid initiating a. Apixaban. ­explains the finding that dabiga-
fondaparinux therapy less than b. Dabigatran etexilate. tran was inferior to enoxaparin
six hours after surgery. c. Idrabiotaparinux. for VTE prevention in patients
c. The need for smaller-than-usual d. Rivaroxaban. undergoing total knee replacement
LMWH doses in critically ill
15. Which of the following is an surgery in the RE-MOBILIZE
patients.
­emerging oral anticoagulant that study but not in the RE-NOVATE
d. The need to avoid removing an
might be particularly useful for study?
epidural catheter during periods
VTE prevention in patients with a. Use of different dabigatran dos-
of peak anticoagulant activity.
renal impairment? ages in the two studies.
11. Which of the following statements
a. Apixaban. b. Use of a shorter duration of
about the use of ultrasound screen-
b. Dabigatran etexilate. treatment in the RE-MOBILIZE
ing for deep vein thrombosis before
c. Idrabiotaparinux. study.
hospital discharge of asymp-
d. Rivaroxaban. c. Use of the more intense North
tomatic patients after surgery
16. Which of the following must be American enoxaparin dosing
is correct?
considered in comparing the results regimen in the RE-MOBILIZE.
a. It is routinely recommended d. Concurrent use of aspirin with
of clinical trials of oral direct
only after major orthopedic dabigatran in the RE-NOVATE
thrombin (factor IIa) and factor
surgery. study.
Xa inhibitors for VTE preven-
b. It is routinely recommended
tion in patients undergoing major
only for morbidly obese patients.
­orthopedic surgery?
a. Differences in the primary
­endpoint and comparator used.

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Continuing Education

19. The use of anticoagulant therapy


for VTE prophylaxis is a concern AJHP Continuing Education
in surgical patients with epidural
Supplement: Improving anticoagu- Test for available tests, listed by topic
catheters for postoperative analgesia
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