Oncology Data Advisor: Prophylaxis of Venous Thromboembolism in the Outpatient Setting

8/3/2019 Oncology Data Advisor: Prophylaxis of Venous Thromboembolism in the Outpatient Setting

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ExpErt AnAlysEs

Identifying Patients Who May

Bt Fro Troboprops

Regina S. Cunningham, PhD, RN, AOCN®

Mount Sna Mdcal Cntr

R t Rs for Rrrt

Vos TrobobosPamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®

Unrsty of Calforna, San Francsco

www.i3Health.com Volume 1 Number 1

DAtA ADVIsOrtM

Interpreting the Science Behind Evidence-Based Cancer Care

Release date: June 15, 2011

Expiration date: June 14, 2012

Educational credit: 1.0 contact hour

Estimated time to complete activity: 60 minutes

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2 www.i3Health.com l Oncolog Data Advisor

Target Audience

Oncolog nurses and other members of the multidisciplinar

cancer care team involved in the prophlaxis and management of

venous thromboembolism (VTE).

Activity Overview

VTE occurs frequentl in patients with cancer and is consideredone of the leading causes of death in this population. This CE-

certied newsletter will review the challenges asssociated with

identifing and managing cancer patients at high risk for throm-

botic complications. Special attention will be given to prophlaxis

strategies in the outpatient setting. Facult will discuss criteria for

identifying patients who may benet from thromboprophlaxis. Se-

lected clinical trials will be presented to inform evidence-based

treatment decision-making for cancer patients at high risk for VTE.

Case studies will be used to illustrate the application of ke stud

ndings in practice.

Learning Objectives

Upon completion of this activit, participants should be able to:

1. Describe the incidence of VTE

2. Identif factors that increase the risk for VTE in patients with

cancer

3. Describe clinical trial data evaluating the safety and efcacy

of anticoagulant therap in patients with cancer

4. Explain how the “P value,” “condence interval,” and “hazard

ratio” can validate clinical trial stud results

FacultyRegina S. Cunningham, PhD, RN, AOCN® (Chairperson)

Mount Sinai Medical Center

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®

Universit of California, San Francisco

Continuing Nursing Education Accreditation

and Contact Hours StatementScience Care is approved b the California Board of Registered

Nursing, Provider number 15559, for 1.0 Contact Hour.

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Nursing, Science Care must ensure balance, independence, ob- jectivity, and scientic rigor in all its activities. All course directors,

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conclusion and resolve any conicts of interest prior to the com -

mencement of the educational activit. Disclosures are as follows:

• Regina S. Cunningham, PhD, RN, AOCN®, has nothing to disclose

• Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®, discloses

relationships with Merck (speaker), Amgen (speaker), and

Novartis (speaker)

• The staff of i3 Health have nothing to disclose

• The staff of Science Care have nothing to disclose

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www.i3Health.com l Oncolog Data Advisor 3

expert analysis

V

enous thromboembolism (VTE) is a com-

mon and potentiall deadl complication

in patients with cancer. VTE has important

clinical implications for patients, including the need

for anticoagulant therap and exposure to its as-

sociated side effects, possible delas in therapeu-

tic interventions, an increased risk for recurrence,

decreased qualit of life, and increased health care

costs. Oncolog nurses are ideall situated to as-

sist in the identication of patients who are at risk

for thrombotic events. It is essential that oncolog

nurses be knowledgeable about risk factors for the

development of VTE, the underling pathophsiol-

og of thromboembolic events, evidence-based

strategies for prophlaxis and management, andpatient education and support interventions. Under-

standing risk is the rst step in identifying patients

who may benet from prophylaxis early, before se-

rious or life-threatening consequences manifest.

In addition, an understanding of the results of im-

portant clinical trials in VTE can facilitate clinical

decision-making for patients at risk for or experi-

encing this complication. Effective management of

patients with thromboembolic events can minimize

associated sequelae, improve qualit of life, and facil-

itate the deliver of a uniform standard of qualit care.

Understanding Risk

The greatest risk for thromboembolic events is seen

among patients who are receiving active cancer

treatment. In one large population-based investi-

gation, the risk for thrombosis was 4.1-fold greater

in patients with cancer and 6.5-fold greater in pa-

tients receiving chemotherap (Silverstein et al, 1998;

Heit et al, 2000). Moreover, in some populations,the risk for VTE decreases dramaticall after che-

motherap has been completed (Levine et al, 1988;

Saphner et al, 1991). Chemotherap can increase

the prothrombotic effects of cancer cells and cause

direct damage to vessel walls; as such, it is in-

creasingly recognized as an important risk factor

Identifying Patients

Who May Benefit From

Thromboprophylaxis

Regina S. Cunningham, PhD, RN, AOCN®

Mount Sinai Medical Center

ABSTRACT

Understanding VE risk is the rst step in identiying cancer patientswho may benet rom prophylaxis early, beore serious or lie-threatening

consequences maniest. Tis brie analysis reviews a VE risk prediction

model developed by Khorana and colleagues and its application in the

ambulatory chemotherapy setting.

Have a question for Dr. Cunningham? E-mail to: [email protected]





expert analysis

for thromboembolic complications (Khorana et al,

2004).

Developing a Risk

Prediction Model

Although a number of specic risk factors have been

identied in the literature (Table 1; NCCN, 2011),

there is limited evidence on how these variables can

be used to develop and/or test predictive models.

Effective prediction models have the potential to as-

sist practicing clinicians in proactivel identifing pa-

tients for whom thromboprophlaxis ma be of most

value. Studies have demonstrated clear benet

associated with prophlactic use of anticoagulation

in certain patients with cancer receiving treatment,

such as those who are undergoing pelvic surger

or who are hospitalized or bedridden; however,

for ver substantial numbers of cancer patients,

such as those receiving chemotherap in the am-

bulator setting, there are limited data on effective

strategies to sstematicall identif and treat those

at risk for this complication. Both the American

Societ of Clinical Oncolog and the American

College of Chest Phsicians have indicated that

additional clinical trials are needed before the can

make an recommendations on the use of anti-

thrombotic prophlaxis in patients receiving chemo-

therap in the ambulator setting (Lyman et al, 2007;

Geerts et al, 2008).

Khorana and colleagues recentl reported on thedevelopment and validation of a predictive model

for chemotherap-associated thrombosis using

data from a multicenter, prospective, observation-

al stud of ambulator cancer patients who were

initiating a new chemotherap regimen. The stud

population included over 4,000 patients who met

the inclusion criteria outlined in Table 2. Patients

were assigned into either the derivation (n=2,701) or

validation (n=1,365) cohorts. The prediction model

was developed based on data from the derivation

cohort. Numerous variables that have been associ-

ated with the development of VTE were assessed,

including demographics, ethnicit, performance

status, comorbidities (eg, mocardial infarction), pe-

ripheral vascular disease, diabetes, and connective

tissue disorders.

Patients were followed prospectivel for a maxi-

mum of four ccles of therap. Sixt patients (2.2%)

developed VTE in the derivation cohort. The vari-

ables that were found to be sttst s-

t associated with the development of smp-

tomatic VTE in this group included primar site of

cancer, prechemotherapy platelet count ≥350 X

109 /L, hemoglobin level <10 g/dL, use of erthro-

poiesis-stimulating agents, leukocyte count >11 X

109 /L, and body mass index ≥35 kg/m2. Among

patients with poor performance status, the ratesof VTE were higher, but this difference did not

achieve statistical signicance. Risk varied by can-

cer site: cancers of the stomach and pancreas were

deemed “ver high risk”; lmphoma, lung, genitouri-

nar (excluding prostate), and gnecologic cancers

were deemed “high risk”; and breast, colorectal,

and head and neck cancers were deemed “low

risk.” Each of the variables in the predictive model

was assigned a score that was used to differentiate

Table 1. Predictors of VTE

RiSk FacTOR

Primar site of cancer

Presence of metastatic disease

Chemotherap

Surger

Hormonal therap

Erthropoiesis-stimulating agents

Presence of a central venous catheter

Based on information from NCCN, 2011.

sttst st: describes a math-

ematical measure of difference between groups.

The difference is said to be statistically signicant

if it is greater than what might be expected to hap-

pen b chance alone 95% of the time. Although

statistically signicant usually refers to 95% con-

dence, sometimes other condence levels such

as 99% or 90% are specied.




expert analysis

patients. A score of 0 was assigned “low risk,” a

score of 1-2 was assigned “intermediate risk,” and

a score of ≥3 was assigned “high risk.”

The rates of VTE in the derivation and validation

cohorts were 0.8% and 0.3%, respectivel, in the

low-risk group; 1.8% and 2% in the intermediate-risk

group; and 7.1% and 6.7% in the high-risk group.

The c-statistic was 0.7 for both cohorts. Based on

these data, the authors concluded that this model

could be used to identif ambulator chemotherap

patients at risk for smptomatic VTE and ma be

used to identif candidates for studies of thrombo-

prophlaxis. The also suggested that additional

studies be undertaken to further test the model.

Thromboprophylaxis in the

High-Risk Ambulatory Patient

A more recent stud used some of the variables

identied by Kohrona and colleagues to select am-

bulator cancer patients receiving chemotherap

for thromboprophlaxis with nadroparin, a low-

molecular-weight heparin (Agnelli et al, 2009). The

objective of this investigation was to assess the

clinical benet of nadroparin in reducing the inci-

dence of thromboembolic events in ambulator

patients with metastatic or locall advanced cancer

receiving chemotherap. Pa-

tients with lung, gastrointesti-

nal (stomach, colon, rectum),

pancreatic, breast, ovarian, or

head and neck cancer were

recruited from 62 centers. Pa-

tients with a recent histor of

thrombotic events, an Eastern

Cooperative Oncolog Group

performance status score >2,

an active bleeding, throm-

boctopenia, an elevated ac-

tivated partial thromboplastin

time ratio, active ulcer disease,

cerebral metastases, severe

hpertension, renal or liver in-

sufciency, or a known hypersensitivity to heparin

were excluded from participation. All patients wererandoml assigned to receive either nadroparin

(3,800 IU anti-Xa) subcutaneously once per day or

a placebo injection in a 2:1 ratio. Patients received

the study drug on the rst day of chemotherapy and

continued for a maximum of 4 months. The primar

outcome of the investigation was the composite

of smptomatic venous or arterial thromboem-

bolic events, as evaluated b an independent re-

view committee. Fifteen (2%) of 769 patients who

c (oor) sttst:

a measure of how well a clini-

cal prediction rule can correctl

rank-order patients b risk. A

model that accuratel discrimi-nates patients 85% of the time

would have a C statistic of 0.85;

with completel random predic-

tions, as in a coin toss, the C sta-

tistic would be 0.5; and a model

that discriminates perfectl be-

tween patients with and without

events would have a C statistic

of 1.0.

incluSiOn cRiTeRia excluSiOn cRiTeRia

Histologically conrmed diagnosis of cancer Receiving concurrent ctotoxic, biologic, or immunologictherap for another condition

Initiating new chemotherap regimen Continuous single-agent therap

Anticipated to complete four ccles of therap Diagnosis of acute leukemia

18 ears of age or older Pregnant or lactating

Able to provide informed consent Active infection requiring treatment

Currentl participating in a double-blind stud

Status post-stem cell transplant

Table 2. Criteria for VTE Prediction Model

Based on information from Khorana et al, 2008.




expert analysis

CASE STUDy: Patient With Cholangiocarcinoma

Mr. WC was a 74-year-old man

who initially presented with abdominal

pain, mild itching, and elevated liverunction tests. Aer a complete work-

up, he was diagnosed with cholangio-

carcinoma. He underwent a surgical

resection o the bile ducts. Te disease

was ound to be invasive with scleros-

ing cholangitis, suggesting a high po-

tential or recurrence. He was reerred

to medical oncology or ollow-up.

Mr. WC’s past medical history

included a history o hypertension,

which was managed with diet, exercise(daily walks), and hydrochlorothiazide.

He reported a history o a deep venous

thrombosis in his le leg secondary to

trauma approximately 11 months pri-

or to his diagnosis. He had no known

allergies to medications or ood. Fam-

ily history was signicant or cardio-

vascular disease: his ather died rom

cardiac disease, and his mother died

rom a stroke. Te patient was mar-

ried with three grown children whowere alive and well. He lived with his

wie who had a limited unctional sta-

tus due to peripheral vascular disease

and diabetes mellitus. Social history

included pipe and cigar smoking 1-2

times per day or a period o approxi-

mately 20 years; he quit 30 years ago.

Alcohol intake was rare (approximate-

ly 1 can o beer per month).

Upon presentation Mr. WC was as-

ymptomatic and in no acute distress.He reported increased atigue since

his surgical procedure and indicated

that he was not as active as he had

been preoperatively. His abdominal

suture line was healing well. Physical

examination revealed ndings within

normal limits with the exception o

slight edema o the lower extremites

bilaterally. Te health care team dis-cussed a plan or adjuvant chemother-

apy with cisplatin and gemcitabine

with the patient and his wie. Te in-

usion nursing sta initiated pretreat-

ment chemotherapy teaching. Assess-

ment o the the patient’s venous access

revealed that he had extremely limited

access or the administration o mul-

tiple (six) cycles o therapy. Te health

care team recommended the insertion

o a subcutaneous central venous ac-cess device. Te patient underwent

insertion o a port-a-cath in interven-

tional radiology the ollowing week

and the rst cycle o chemotherapy

was initiated. Te patient received pre-

hydration with normal saline and an-

tiemetics that included palonosetron,

aprepitant, and dexamethasone. In

addition, he received antiemetic pre-

scriptions to manage delayed nausea

and vomiting. Te ollowing laborato-ry parameters were measured prior to

chemotherapy: white blood cell count,

7,200/µL; hemoglobin, 13.5 g/dL; he-

maotcrit, 42%; platelets, 354,000/µL;

and creatinine, 1.1 mg/dL.

Chemotherapy was administered

without consequence. Te therapy

was well tolerated by the patient. An-

ticipatory care was reviewed prior to

discharge and the patient demonstrat-

ed a good understanding o sel-carestrategies. He was provided with the

number or the Nurse Help Line and

instructed to call with any questions

or problems.

Mr. WC’s risk or thromboembol-

ic complications included a primary

diagnosis o a gastrointestinal ma-

lignancy that was treated with both

surgery and chemotherapy; in addi-tion, he had a pretreatment platelet

count o 354,000/µL, a central venous

catheter, and a history o a relatively

recent thromboembolic event. Al-

though these risks were documented,

Mr. WC did not receive thrombopro-

phylaxis. Currently, the prophylactic

use o anticoagulants to prevent em-

bolic events in the ambulatory che-

motherapy population has not been

substantiated by strong evidencegenerated through randomized clini-

cal trials. Te study by Agnelli and

colleagues (2009) begins to address

this issue and provides some evi-

dence that thromboprophylaxis with

the low-molecular-weight heparin

nadroparin is eective in reducing

thromboembolic events in ambula-

tory chemotherapy patients who are

at greater risk or developing these

complications; however, it is impor-tant to note that the exclusion criteria

included adjuvant chemotherapy and

recent (dened as within 3 months)

venous or arterial thrombotic events.

Tereore, Mr. WC would not have

met the eligibility criteria or enroll-

ment. Additional clinical trials are

needed beore global recommenda-

tions about thromboprophylaxis in

ambulatory chemotherapy patients at

high risk or thrombotic events canbe made.

Mr. WC completed six cycles o

therapy without diculty. During

his last oce visit, he was noted to be

doing well with no evidence o active

disease.




expert analysis

received nadroparin and 15 (3.9%) of 381 patients

who received placebo developed thromboembolic

events. Five patients in the nadroparin group expe-

rienced a major bleeding event versus none in the

placebo group. Major bleeding events were denedas fatal or clinicall overt events. The incidence of

minor bleeding events was comparable across the

treatment groups. The authors concluded that the

administration of prophlactic nadroparin in this

high-risk population was effective in decreasing the

rate of thrombotic complications b approximatel

50%. The benet was most evident in patients with

lung and gastrointestinal malignancies.

Patient Education, Support,

and Safety

Effective management of patients receiving VTE

prophlaxis includes the provision of appropri-

ate safet measures as well as timel and relevant

education (Cunningham, 2005). Anticoagulation is an

intervention that requires patient understanding,

cooperation, and adherence over time. Medication

education and monitoring are essential elements

of treatment planning to reduce the risk of adverse

events associated with anticoagulant therap. The

Joint Commission has identied the provision of

detailed information to patients about their medica-

tion as a National Patient Safet Goal. Patients and

families should be educated on the potential com-

plications of anticoagulant agents. If low-molecular-

weight heparin is selected for prophlaxis, the pa-

tient (or a famil member) must be taught how to

administer subcutaneous injections. Monitoring

plans should also be carefull reviewed.

onclusion

VTE is a common and serious complication in

cancer patients undergoing treatment in the am-

bulator setting. Clearl, the availabilit of an em-

piricall validated model to identif appropriate

candidates for thromboprophlaxis would be of substantial benet to practicing clinicians. In ad-

dition, more data are needed to identif the opti-

mal method of prophlaxis for patients who are

at high risk. Oncolog nurses need to be aware

of the potential for VTE, be involved in the iden-

tication of patients at risk, and keep abreast of

emerging data from clinica l trials that have the po-

tential to affect practice.

Disclosures

Regina S. Cunningham, PhD, RN, AOCN® has

nothing to disclose.

No writing assistance was utilized in the production

of this manuscript.

REFERENCES

Agnelli G, Gussoni G, Bianchini C, et al (2009). Nad-

roparin for the prevention of thromboembolic events in

ambulator patients with metastatic locall advanced

solid cancer receiving chemotherap: a randomised,

placebo-controlled, double-blind stud. The Lancet

Oncology, 10, 943-949.

Cunningham RS. (2005). Therapeutic options for the

treatment of cancer-associated thrombosis. Seminars

in Oncology Nursing, 21, 21-40.

Geerts WH, Bergqvist D, Pineo GF, et al (2008). Pre-

vention of venous thromboembolism: American Collegeof Chest Phsicians Evidence-Based Clinical Practice

Guidelines (8th Edition). Chest, 133(6 Suppl):381S-

453S.

Heit JA, Silverstein MD, Mohr DN, et al (2002). Risk fac-

tors fro deep vein thrombosis and pulmonar embolism:

a population-based case-control stud. Archives of

Internal Medicine, 160, 809-815.

Khorana AA, Francis CW, Culakova E, Lman GH

(2005). Risk factors for chemotherap associated ve-

nous thromboembolism in a prospective observational

stud. Cancer, 104, 2822-2829.

Khorana AA, Kuderer NM, Culakova E, et al (2008).

Development and validation of a predictive model for

chemotherap-associated thrombosis. Blood, 211,4902-4907.

Levine MN, Gent M, Hirsh J, et al (1988). The thrombo-

genic effect of anticancer therap in women with stage

II breast cancer. New England Journal of Medicine, 318,

404-407.

Lman, GH, Khorana AO, Falanga A, et al (2007). Amer-

ican Societ of Clinical Oncolog Guideline: Recom-

mendations for venous thromboembolism prophlaxis

and treatment in patients with cancer. Journal of Clinical

Oncology, 25:5490-5505.

National Comprehensive Cancer Network (2011). Clini-

cal practice guidelines in oncolog: venous thrombo-

embolic disease. Version 2.2011. Accessed from http://

www.nccn.org.

Saphner T, Torme DC, Gra R (1991). Venous and

arterial thrombosis in patients who received adjuvant

therap for breast cancer. Journal of Clinical Oncology,

9, 286-294.

Silverstein MD, Heit JA, Mohr DN, et al (1998).

Trends in the incidence of deep vein thrombo-

sis and pulmonar embolism: a 25-ear popula-

tion based stud. Archives of Internal Medicine, 158,

585-593. l




expert analysis

Venous thromboembolism (VTE) occurs

frequentl in patients with cancer and is

considered one of the leading causes of

death in this population (Lyman et al, 2007). Despite

the serious threat, VTE often is underdiagnosed and

undertreated (Falanga & Zacharski, 2005). Thrombosis

may occur as the rst manifestation of neoplastic

disease and is associated with signicant morbidity

and mortalit in patients with cancer. The incidence

of VTE observed during autops has been reported

to be as high as 50% to 60% versus 4% to 20% in

patients observed clinicall (Lyman et al, 2007; Shen

& Pollak, 1980). Patients with cancer who are hospi-

talized or receiving active therapy for their disease

are at increased risk (Lyman et al, 2007). Factors that

contribute to the risk for VTE in patients with cancer

include stage of disease, tumor tpe, chemothera-

p and hormonal therap, surger or trauma, and

the presence of a central venous catheter (Linkins, 2008). Once a patient develops VTE, the risk for a

recurrent event is high (Lyman et al, 2007). Therefore

it is of great interest to researchers and clinicians

to determine optimal strategies for VTE prevention

and treatment.

Scope of the Problem

Antithrombotic therap in patients with cancer is

clinicall challenging. Once these patients develop

VTE, the are at higher risk for recurrent VTE events

compared with patients without a cancer diagnosis

(Buller et al, 2004). Historicall, management of VTE in

patients with cancer required initial treatment with

heparin (Falanga & Zacharski, 2005). Anticoagulation

with heparin involved a subcutaneous injection of

weight-adjusted low-molecular-weight or unfrac-

tionated heparin b intravenous infusion, with thera-

p lasting 5 to 7 das. This period was followed b

vitamin K antagonist therap with warfarin or a simi-

lar agent, adjusted to provide an international nor-

malized ratio (INR) of 2.0 to 3.0, with therapy last -

ing approximatel 3 to 6 months (Buller et al, 2004).

Recent data suggest that thromboprophlactic

therap following an initial VTE event in patients with

malignancy should be administered indenitely, orfor at least as long as the cancer is active (Zacharski,

Prandoni, & Monreal, 2005; Levine, 2002). Additionall,

low-molecular-weight heparin is currentl preferred

as an effective and safe treatment for prophlaxis

and management of VTE (Karimi & Cohan, 2010).

Reducing the Risk for Recurrent

Venous ThromboembolismPamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®

University of California, San Francisco

ABSTRACT

Patients with cancer are at increased risk or recurrent VE compared

with patients without a cancer diagnosis. Tis commentary reviews

key ndings rom the CLO trial, which evaluated the role o low-molecular-weight heparin in preventing VE, and their implications

or oncology nursing practice.

Have a question for Ms. Viale? E-mail to: [email protected]





expert analysis

In patients without cancer, warfarin is considered

to be the mainsta of therap for oral anticoagu-

lation but complications can occur with this agent

(Pangilinan, Pangilinan, & Worden, 2007; Zacharski, Pran-

doni, & Monreal, 2005). The drug is rapidl absorbedwith a long half-life of 36 to 42 hours (Hirsh, Fuster,

Ansell et al, 2003). Warfarin has a narrow therapeutic

window, and its efcacy can be affected by genetic

polmorphisms, dietar intake, and drug-drug in-

teractions requiring frequent monitoring and dose

adjustments for even uncomplicated patients (Pang-

ilinan, Pangilinan, & Worden, 2007; Zacharski, Prandoni, &

Monreal, 2005). In patients with cancer, the scope of

complications is considerabl expanded.

hallenges With Warfarin Therapy

as Secondary ProphylaxisIn one communit-based trial of patients receiving war-

farin for a variet of reasons, patients with active cancer

spent less time in their target INR ranges, showed more

variable INR values, required more frequent INR testing,

and experienced more thrombotic events compared

with patients without a diagnosis of malignanc (Rose et

al, 2007). The rate of complications can be higher in pa-

tients with cancer who receive warfarin therap. An in-

creased incidence of bleeding has been demonstrated

in several studies (Zacharski, Prandoni, & Monreal, 2005).

Risk factors such as duration of therap, recent surger-

ies or trauma, older age (>65 ears), and renal or he-

patic dsfunction ma contribute to the increased risk

for bleeding (Zacharski, Prandoni, & Monreal, 2005). The

therapeutic window can be difcult to achieve in pa-

tients with cancer, as patients ma require interruptions

of therap due to the need for procedures or because

the experience treatment-related thromboctopenia

(Falanga & Zacharski, 2005). Patients with cancer ma

experience recurrent thrombosis despite treatment with

warfarin because of changes in nutritional status, drug

interactions, and alterations in liver metabolism, which

ma result from the cancer or its treatment (Falanga &

Zacharski, 2005). Because of these factors, improve-

ments in anticoagulation for patients with cancer areneeded. Secondar prophlaxis with LMWH offers an

alternative method of anticoagulation.

The Significance of the OT Study

The CLOT (Comparison of Low molecular weight

heparin versus Oral anticoagulant Therap) stud

was the rst large-scale trial to compare the safety

and efcacy of LMWH and warfarin therapy in the

prevention of recurrent VTE in patients with can-

cer (Lee et al, 2003) (Table 1). This pivotal trial dem-

onstrated that the risk for smptomatic, recurrent

thromboembolism in patients with cancer was sig-nicantly reduced with the administration of dalte-

parin LMWH compared with traditional oral antico-

agulant therap with warfarin (Lee et al, 2003).

Stud participants were patients with cancer who

had acute, smptomatic proximal deep vein throm-

bosis (DVT), pulmonar embolism (PE), or both.

Patients were randoml assigned to either LMWH

(dalteparin) at a dose of 200 IU per kg of bod

weight subcutaneousl once dail for 5 to 7 das

and a coumarin derivative (warfarin or acenocouma-

rol) for 6 months (target INR, 2.5) or dalteparin alone

for 6 months (200 IU per kg once dail for 1 month,

followed b a dail dose of approximatel 150 IU

per kg for 5 months). Intensive anticoagulation was

provided at the start of the regimen followed b a

reduced-dose therap, with the goal of reducing the

risks (eg, bleeding) of anticoagulant therap in this

patient population.

The results of the stud showed:

• During the 6-month stud period, 27 of

336 patients in the dalteparin group expe-

rienced recurrent VTE versus 53 of 336 pa-

tients in the oral anticoagulant therap group

(zr rto, 0.48; P=0.002)

• The probabilit of recurrent

thromboembolism at 6 months

was 17% in the oral anticoag-

ulant therap group compared

with 9% in the dalteparin group

• No signicant differences were

noted between the daltepa-

rin group and the oral antico-

agulant group in rate of major

bleeding (6% vs 4%, respec-

tivel) or an bleeding (14% vs

19%, respectivel)

• The mortalit rate in the daltepa-

rin group at 6 months was 39%compared with 41% in the oral

anticoagulant therap group

The P value for the number of

recurrent VTE events indicated that

the results of the study were signicant (Table 2).

Strengths of this study included the randomized

controlled trial design, which is considered the

gold standard in clinical research, and the evenl

zr rto: hazard ratios

are often used to measure

survival at an point in time in

a group of patients who have

been given a specic treat-

ment compared with a control

group given another treatment

or placebo. A hazard ratio of

1.0 means that there is no dif-

ference in survival between the

two groups. A hazard ratio of

greater than 1 or less than 1means that survival was better

in one of the groups.




expert analysis

STudy auThORS STudy deSign ReSulTS imPlicaTiOnS

mr t , 2002

CANTHANOX

Stud

Open-label, multicenter, ran-

domized trial involving 146

cancer patients receiving ei-

ther enoxaparin LMWH or

warfarin for 3 months

Of 71 evaluable patients re-

ceiving warfarin, 15 (21.1%)

experienced one major out-

come event vs 7 (10.5%) in the

stud arm. A total of 6 deaths

occurred from hemorrhage in

the warfarin group vs 0 in the

LMWH group; 17 deaths oc-

curred in the warfarin group vs

8 in the LMWH group.

Warfarin in cancer patients

who develop a VTE is associ-

ated with a high bleeding rate;

LMWH ma be as effective as

oral anticoagulants and ma

be safer. Larger studies are

needed to conrm ndings.

l t , 2003

CLOT Stud Open-label, multicenter, ran-

domized trial involving 676

cancer patients assigned to

dalteparin 200 U/kg followed

b maintenance LMWH 150

U/kg (treatment time, 6 mo)

or dalteparin followed b oral

anticoagulation

Follow-up at end of stud

period of 6 months showed

that 27 of 336 patients in the

dalteparin group had recur-

rent VTE vs 53 of 336 patients

in oral anticoagulant group

(HR, 0.48; 95% CI, 0.30-0.77;

P =0.002)

Patients receiving daltepa-

rin initiall followed b main-

tenance LMWH had lower

recurrence rates of VTE, al-

though rates of bleeding and

death at 6 months were not

signicantly different between

the two groups

h t , 2006

LITE Stud Open-label, multicenter, ran-

domized trial with 200 pa-

tients receiving either tinza-

parin LMWH or vitamin-K

antagonist therap for 3

months; outcomes were as-

sessed at 3 and 12 months

At 12 months, the control

group had 16% recurrent

VTE episodes vs 7% in the

LMWH group (P =0.44; risk

ratio, 0.44; 95% CI, -21.7-

10.7); minor bleeding (27%)

occurred in the LMWH group

versus 24% in the control

group (95% CI, -9.1-15.1).

Major bleeding occurred in0% of the LMWH group com-

pared with 2.1% in the control

group; mortalit was equal for

both (47%).

The P value was not signi-

cant at 3 months, but was

0.44 at 1 ear; the authors

concluded that their ndings

conrm the limited exist-

ing data indicating LMWH is

more effective than vitamin

K antagonist therap for the

prevention of VTE in cancer

patients; mortalit was notaffected.

Table 1. LMWH vs Oral Anticoagulant Therap in the Prevention of VTE Recurrence

LMWH = low-molecular-weight heparin; VTE = venous thromboembolism; HR = hazard ratio; CI = condence interval.




expert analysis

balanced stud groups. Limitations included its

open-label versus blinded design, which could

have introduced bias into the results. In addition,

the manufacturer of the stud drug, dalteparin, was

the sponsor. However, as the authors indicated, adouble-blinded stud design could have been un-

safe for patients who had comorbid conditions and

were taking multiple concomitant agents potentiall

increasing their risk for drug interactions (Lee et al,

2003).

The results demonstrated that the stud drug

essentiall cut in half the risk for recurrent throm-

boembolism compared with the conventional

therap of LMWH followed b oral anticoagulant

therap. In addition, the new therap did not in-

crease the risk for bleeding (although the two

groups had virtuall the same amount of bleed-

ing). At 6 months 130 patients (39%) died in the

dalteparin group versus 136 (41%) in the oral anti-

coagulant therap group. Progressive cancer was

the cause of death for 90% of the deaths in both

groups (Lee et al, 2003).

onclusion

Based on data from the pivotal trials examin-

ing the efficac of LMWH compared with oral

anticoagulant therap, National Comprehen-

sive Cancer Network guidelines recommend

LMWH (dalteparin, enoxaparin, tinzaparin),

fondaparinux, or unfractionated heparin as ini-

tial treatment for VTE; LMWH is also recom-

mended as the preferred treatment for chronic

management of VTE for the first 6 months as

monotherap without warfarin in patients with

proximal VTE or PE and the prevention of

STudy Value deScRiPTiOn examPle FROm The clOT STudy

P V Statistical inference requires beginning with

the hpothesis that there is no difference

between a treatment group and a control

group. The P value helps us calculate the

probabilit that the difference demonstrat-

ed in a stud occurred because of chance.

Statistical signicance usually requires a P

value of 0.05 or less.

27 of 336 patients in the dalteparin group

had recurrent VTE versus 53 of 336 patients

in the oral anticoagulant therap group (HR,

0.48; P =0.002). This P value indicates that

there is 0.002 chance that the results in the

trial occurred b chance and thus is a sig-

nicant nding.

hzr rto Refers to the rate at which events happen;

the HR is an expression of the hazard or

chance of events occurring in the treatment

arm as a ratio of the hazard of the events

occurring in the control arm. HR >1.0 indi-

cates increased risk rate; HR <1.0 indicates

decreased risk rate.

Measuring the difference between the stud

group and the control group in the CLOT

stud, the HR was 0.48. This indicates that

the risk was decreased for the stud group

(a 52% reduction in the risk for recurrent

VTE) compared with the warfarin group, a

signicant nding of the investigation.

co trv A range around a measurement that dem-

onstrates how precise the measurement is.

In examining the probabilit of smptom-

atic VTE in patients with cancer, the HRwas 0.48 with a 95% CI. If the CI had been

a ver wide range, the data would not be

considered as signicant. With a 95%

CI, there is a 5% chance that the results

are incorrect.

Table 2. Understanding Statistical Analsis Via the CLOT Stud

Based on information from Norman et al, 2009. VTE = venous thromboembolism; HR = hazard ratio;

CI = condence interval.




expert analysis

Based on information from Falanga & Zarcharski, 2005. VKAs = vitamin K antagonists;

INR = International Normalized Ratio.

lmWh Vka s

dos Bod weight-adjusted dose; no

need for laborator monitoring.

Given as subcutaneous injection.

Titrated dose to achieve thera-

peutic INR (most commonl 2.0-

3.0)

Oral administration

ept rspos Predictable anticoagulant re-

sponse with rapid bioavailabilit

after injection; twice dail or once

dail formulations available

Dose must be adjusted frequentl

in most patients to achieve INR

Pott for

r-r trtos

Therapeutic response not affect-

ed b concomitant medications

or diet

Drug-drug and drug-diet interac-

tions common with VKAs

Table 3. LMWH vs Vitamin K Antagonists

recurrent VTE in patients with advanced or met-

astatic cancer (NCCN, 2010). The minimum rec-

ommended duration of anticoagulation therap

is 3 to 6 months for VTE and 12 months for PE;

indefinite anticoagulation is recommended forpatients with active cancer or persistent risk

factors (NCCN, 2011). The American Societ of

Clinical Oncolog and the European Societ for

Medical Oncolog have developed similar guide-

lines incorporating LMWH as well (Khorana, 2009;

Lyman et al, 2007).

Patients with cancer are at risk for VTE due

to a mriad of factors, including active disease

and chemotherap treatment. Oral anticoagu-

lants such as warfarin have been used to treat

VTE in patients with cancer; however, achieving

and maintaining therapeutic INRs in this popula-

tion is inherentl difficult as underanticoagulation

and supratherapeutic results are common (Table

3) (Hull et al, 2006; Meyer et al, 2002). LMWH has

demonstrated efficac and safet in the treat-

ment of cancer patients who develop VTE. Ad-

ditional trials are needed to continue to define the

role of LMWH and the benefits of therap in this

population.

Disclosures

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®,

discloses relationships with Merck (speaker),

Amgen (speaker), and Novartis (speaker).

No writing assistance was utilized in the productionof this manuscript.

REFERENCES

Falanga A & Zacharski L. (2005). Deep vein thrombo-

sis in cancer: the scale of the problem and approaches

to management. Annals of Oncology, 16, 696-701.

doi:10.1093/annonc/mdi165

Hirsh J, Fuster V, Ansell J, & Halperin JL (2003). American

Heart Association/American College of Cardiolog

Foundation guide to warfarin therap. Circulation, 107,

1692-1711.

Hull RD, Pineo GF, Brant RF, et al; LITE Trial Investiga-

tors (2006). Long-term low-molecular-weight heparinversus usual care in proximal-vein thrombosis patients

with cancer. The American Journal of Medicine, 119

(12), 1062-1072.

Khorana AA (2009). Cancer and thrombosis: impli-

cations of published guidelines for clinical practice.

Annals of Oncology, 20, 1619-1630. doi:10.1093/

annonc/mdp068

Lee Ayy, Levine MN, Baker RI, et al (2003). Low-molecular




expert analysis

weight heparin versus a coumarin for the prevention

of recurrent venous thromboembolism in patients with

cancer. The New England Journal of Medicine, 349 (2),

146-153.

Levine MN (2002). Managing thromboembolic disease

in the cancer patients: efcacy and safety of antithrom-

botic treatment options in patients with cancer. Cancer

Treatment Reviews, 28, 145-149.

Linkins L-A (2008). Management of venous thrombo-

embolism in patients with cancer: role of dalteparin.

Vascular Health and Risk Management , 4 (2), 279-287.

Lman GH, Khorana AA, Falanga A, et al (2007). Ameri-

can Societ of Clinical Oncolog Guideline: Recom-mendations for venous thromboembolism proph-

laxis and treatment in patients with cancer. Journal

of Clinical Oncology, 25, 55490-5505. doi:10.1200/

JCO.2007.14.1283

Meer G, Marjanovic Z, Valcke J, et al (2002). Compari-

son of low-molecular-weight heparin and warfarin for

the secondar prevention of venous thromboembolism

in patients with cancer: a randomized controlled study.

Archives of Internal Medicine, 162 (15), 1729-1735.

National Comprehensive Cancer Network (2011). Clini-

cal practice guidelines in oncolog: venous thrombo-

embolic disease. Version 2.2011. Accessed from http://

www.nccn.org.

Norman, GR & Steiner DL. (2009). P less than 0.05:

statistical inference. Community Oncology, 6 (6), 284-

286. Accessed from http://www.comunitoncolog.net.

Pangilinan JM, Pangilinan PH, & Worden FP. (2007).

Use of warfarin in the patient with cancer. The Journal

of Supportive Oncology, 5 (3), 131-136.

Rose AJ, Sharman JP, Ozonoff A, et al (2007). Effec-tiveness of warfarin among patients with cancer. Jour-

nal of General Internal Medicine, 22 (7), 997-1002.

doi:10.1007/s11606-007-0228-

Zarcharski LR, Prandoni P, & Monreal (2005). Warfarin

versus low-molecular-weight-heparin therap in cancer

patients. The Oncologist, 10, 72-79. l

Mr. Santos was a 56-year-old man

with a diagnosis o metastatic colorec-

tal cancer to the liver. He was started

on FOLFOX (5-fuorouracil, leucovo-

rin, and oxaliplatin) chemotherapy

aer the placement o an indwelling

vascular access device. His baseline

perormance status was poor, with a

Karnosky rating o 70. Te patient

was receiving multiple medications

or comorbid conditions. Mr. San-

tos had ew caregivers to assist him athome and relied on riends to bring

him to treatment. One riend reported

that Mr. Santos’ activity level was very

low, with much o his time spent lying

down or resting, and diet very poor.

Although this riend encouraged him

to be more active, Mr. Santos had di-

culty walking even short distances

because he oen elt very atigued and

had nausea and mild-to-moderate

neuropathy symptoms related to his

oxaliplatin therapy. At his third visit

to the clinic, Mr. Santos arrived in a

wheelchair with new complaints o le

leg pain and swelling. Aer assessment

and physical examination by the oncol-

ogy nurse practitioner, he underwent

Doppler ultrasonography o his le

leg to rule out lower extremity VE.

est results were positive, leading toa diagnosis o a large near-occlusive

popliteal VE. Aer discussion with

Mr. Santos and his riend, the health

care team initiated treatment or the

VE with LMWH ollowed by mainte-

nance LMWH. With his active cancer

(indicated by his metastatic disease),

the health care team elt Mr. Santos

would have a reduced risk or VE re-

currence with LMWH. Adherence to

oral anticoagulation therapy and the

potential or drug interactions were

also considerations in the treatment

planning. Mr. Santos was receiving a

5-fuorouracil–based regimen, which

had the potential to interact with oral

wararin (Khorana, 2009). Key actors

in the therapeutic decision-making

process included the act that Mr. San-

tos agreed to learn sel-injection tech-niques with the aid o his riend, who

had decided to move in with him and

act as a caregiver. In addition, Mr. San-

tos’ neuropathy symptoms precipitated

a change to irinotecan-based chemo-

therapy with FOLFIRI and the adjust-

ment o his antiemetics to improve

control o his nausea.

CASE STUDy:Patient With Metastatic Colorectal Cancer



001VTE

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Oncology Data Advisor: Prophylaxis of Venous Thromboembolism in the Outpatient Setting