O n c O l O g y DAtA ADVIsOr

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Interpreting the Science Behind Evidence-Based Cancer Care

Volume 1 Number 1

Prophylaxis of Venous Thromboembolism in the Outpatient Setting

ExpErt AnAlysEs

Identifying Patients Who May Benefit From Thromboprophylaxis

Regina S. Cunningham, PhD, RN, AOCN Mount Sinai Medical Center

Reducing the Risk for Recurrent Venous Thromboembolism

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP University of California, San Francisco

Release date: June 15, 2011 Expiration date: June 14, 2012 Educational credit: 1.0 contact hour Estimated time to complete activity: 60 minutes

This activity is supported by an independent educational grant from Eisai Inc. 2011 i3 Health. All rights reserved.

ACCREDITATION INFORMATION
Target Audience
Oncology nurses and other members of the multidisciplinary cancer care team involved in the prophylaxis and management of venous thromboembolism (VTE).

Commercial Support

This activity is supported by an independent educational grant from Eisai, Inc.

Activity Overview

Disclosure of Conflicts of Interest

VTE occurs frequently in patients with cancer and is considered one of the leading causes of death in this population. This CEcertified newsletter will review the challenges asssociated with identifying and managing cancer patients at high risk for thrombotic complications. Special attention will be given to prophylaxis strategies in the outpatient setting. Faculty will discuss criteria for identifying patients who may benefit from thromboprophlaxis. Selected 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 key study findings in practice.

Learning Objectives

Upon completion of this activity, participants should be able to: 1. Describe the incidence of VTE 2. Identify factors that increase the risk for VTE in patients with cancer 3. Describe clinical trial data evaluating the safety and efficacy of anticoagulant therapy in patients with cancer 4. Explain how the P value, confidence interval, and hazard ratio can validate clinical trial study results

As a provider accredited by the California Board of Registered Nursing, Science Care must ensure balance, independence, objectivity, and scientific rigor in all its activities. All course directors, faculty, planners, and any other individual in a position to control the content of this educational activity are required to disclose to the audience any relevant financial relationships with any commercial interest. Science Care must determine if the facultys relationships may influence the educational content with regard to exposition or conclusion and resolve any conflicts of interest prior to the commencement of the educational activity. 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

Method of Participation

Faculty

Regina S. Cunningham, PhD, RN, AOCN (Chairperson) Mount Sinai Medical Center Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP University of California, San Francisco

1. Go to www.i3Health.com and login or register for a FREE account 2. Select CME/CE Activities from the main menu 3. Select this newsletters title from the list shown 4. Complete the activity learning path 5. Follow the link to complete the posttest and activity evaluation 6. Print your Certificate of Credit

This activity is provided free of charge to participants.

Continuing Nursing Education Accreditation and Contact Hours Statement

Disclaimer

Science Care is approved by the California Board of Registered Nursing, Provider number 15559, for 1.0 Contact Hour.

The opinions and recommendations expressed by faculty, authors, and other experts whose input is included in this activity are their own and do not necessarily represent the viewpoint of Science Care LLC or i3 Health LLC.

Oncology Data Advisor is published by i3 Health LLC, 184 South Livingston Avenue, Suite 9-268, Livingston, NJ 07039. Copyright 2011 by i3 Health LLC. All rights reserved. No part of this publication may be reproduced or transmitted in any form by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or an informational storage and retrieval system, without written permission from the publisher. Publisher Note: This newsletter is based on presentations by hematology/oncology experts, and the material presented herein is intended to be a thorough, objective, balanced presentation of clinical information. The opinions expressed in this publication are those of the authors, presenters, and/or panelists or may be derived from the professional literature or other clinical sources and are not necessarily the same as indicated in the prescribing information for the product(s) discussed. This publication may contain discussion of off-label uses of commercial products or investigational uses not cleared for marketing. Readers are advised to consult the official prescribing information for discussion of approved indications, contraindications, and warnings before administering any product. Cover photo credit: Andrea Danti/shutterstock.com 2

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Identifying Patients Who May Benefit From Thromboprophylaxis

Regina S. Cunningham, PhD, RN, AOCN
Mount Sinai Medical Center

ABSTRACT

Understanding VTE risk is the first step in identifying cancer patients who may benefit from prophylaxis early, before serious or life-threatening consequences manifest. This brief analysis reviews a VTE risk prediction model developed by Khorana and colleagues and its application in the ambulatory chemotherapy setting.

enous thromboembolism (VTE) is a common and potentially deadly complication in patients with cancer. VTE has important clinical implications for patients, including the need for anticoagulant therapy and exposure to its associated side effects, possible delays in therapeutic interventions, an increased risk for recurrence, decreased quality of life, and increased health care costs. Oncology nurses are ideally situated to assist in the identification of patients who are at risk for thrombotic events. It is essential that oncology nurses be knowledgeable about risk factors for the development of VTE, the underlying pathophysiology of thromboembolic events, evidence-based strategies for prophylaxis and management, and patient education and support interventions. Understanding risk is the first step in identifying patients who may benefit from prophylaxis early, before serious or life-threatening consequences manifest. In addition, an understanding of the results of important clinical trials in VTE can facilitate clinical

decision-making for patients at risk for or experiencing this complication. Effective management of patients with thromboembolic events can minimize associated sequelae, improve quality of life, and facilitate the delivery of a uniform standard of quality care.

Understanding Risk
The greatest risk for thromboembolic events is seen among patients who are receiving active cancer treatment. In one large population-based investigation, the risk for thrombosis was 4.1-fold greater in patients with cancer and 6.5-fold greater in patients receiving chemotherapy (Silverstein et al, 1998; Heit et al, 2000). Moreover, in some populations, the risk for VTE decreases dramatically after chemotherapy has been completed (Levine et al, 1988; Saphner et al, 1991). Chemotherapy can increase the prothrombotic effects of cancer cells and cause direct damage to vessel walls; as such, it is increasingly recognized as an important risk factor

Have a question for Dr. Cunningham? E-mail to: editor@i3health.com 2011 i3 Health. All rights reserved.

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2004).

for thromboembolic complications (Khorana et al,

Developing a Risk Prediction Model

Although a number of specific risk factors have been identified 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 assist practicing clinicians in proactively identifying patients for whom thromboprophylaxis may be of most value. Studies have demonstrated clear benefit associated with prophylactic use of anticoagulation in certain patients with cancer receiving treatment, such as those who are undergoing pelvic surgery or who are hospitalized or bedridden; however, for very substantial numbers of cancer patients, such as those receiving chemotherapy in the ambulatory setting, there are limited data on effective strategies to systematically identify and treat those at risk for this complication. Both the American Society of Clinical Oncology and the American College of Chest Physicians have indicated that additional clinical trials are needed before they can Table 1. Predictors of VTE

Geerts et al, 2008).

make any recommendations on the use of antithrombotic prophylaxis in patients receiving chemotherapy in the ambulatory setting (Lyman et al, 2007; Khorana and colleagues recently reported on the development and validation of a predictive model for chemotherapy-associated thrombosis using data from a multicenter, prospective, observational study of ambulatory cancer patients who were initiating a new chemotherapy regimen. The study 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 associated with the development of VTE were assessed, including demographics, ethnicity, performance status, comorbidities (eg, myocardial infarction), peripheral vascular disease, diabetes, and connective tissue disorders. Patients were followed prospectively for a maximum of four cycles of therapy. Sixty patients (2.2%) developed VTE in the derivation cohort. The variables that were found to be statistically significantly associated with the development of symp-

statistically significant: describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone 95% of the time. Although statistically significant usually refers to 95% confidence, sometimes other confidence levels such as 99% or 90% are specified.

RiSk FacTOR
Primary site of cancer Presence of metastatic disease Chemotherapy Surgery Hormonal therapy Erythropoiesis-stimulating agents Presence of a central venous catheter Based on information from NCCN, 2011.

tomatic VTE in this group included primary site of cancer, prechemotherapy platelet count 350 X 109/L, hemoglobin level <10 g/dL, use of erythropoiesis-stimulating agents, leukocyte count >11 X 109/L, and body mass index 35 kg/m2. Among patients with poor performance status, the rates of VTE were higher, but this difference did not achieve statistical significance. Risk varied by cancer site: cancers of the stomach and pancreas were deemed very high risk; lymphoma, lung, genitourinary (excluding prostate), and gynecologic 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 www.i3Health.com Oncology Data Advisor
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Table 2. Criteria for VTE Prediction Model

incluSiOn cRiTeRia
Histologically confirmed diagnosis of cancer

excluSiOn cRiTeRia
Receiving concurrent cytotoxic, biologic, or immunologic therapy for another condition Continuous single-agent therapy Diagnosis of acute leukemia Pregnant or lactating Active infection requiring treatment Currently participating in a double-blind study Status post-stem cell transplant

Initiating new chemotherapy regimen Anticipated to complete four cycles of therapy 18 years of age or older Able to provide informed consent

Based on information from Khorana et al, 2008. 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%, respectively, 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 identify ambulatory chemotherapy patients at risk for symptomatic VTE and may be used to identify candidates for studies of thromboprophylaxis. They also suggested that additional studies be undertaken to further test the model. receiving chemotherapy. Pac (concordance) statistic: tients with lung, gastrointestia measure of how well a clininal (stomach, colon, rectum), cal prediction rule can correctly pancreatic, breast, ovarian, or rank-order patients by risk. A head and neck cancer were model that accurately discrimirecruited from 62 centers. Panates patients 85% of the time tients with a recent history of would have a C statistic of 0.85; thrombotic events, an Eastern with completely random predicCooperative Oncology Group tions, as in a coin toss, the C staperformance status score >2, tistic would be 0.5; and a model any active bleeding, thromthat discriminates perfectly bebocytopenia, an elevated actween patients with and without tivated partial thromboplastin events would have a C statistic time ratio, active ulcer disease, of 1.0. cerebral metastases, severe hypertension, renal or liver insufficiency, or a known hypersensitivity to heparin were excluded from participation. All patients were randomly 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 first day of chemotherapy and continued for a maximum of 4 months. The primary outcome of the investigation was the composite of symptomatic venous or arterial thromboembolic events, as evaluated by an independent review committee. Fifteen (2%) of 769 patients who

Thromboprophylaxis in the High-Risk Ambulatory Patient

A more recent study used some of the variables identified by Kohrona and colleagues to select ambulatory cancer patients receiving chemotherapy for thromboprophylaxis with nadroparin, a lowmolecular-weight heparin (Agnelli et al, 2009). The objective of this investigation was to assess the clinical benefit of nadroparin in reducing the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer www.i3Health.com Oncology Data Advisor
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CASE STU D y: Patient With Cholangiocarcinoma

Mr. WC was a 74-year-old man who initially presented with abdominal pain, mild itching, and elevated liver function tests. After a complete workup, he was diagnosed with cholangiocarcinoma. He underwent a surgical resection of the bile ducts. The disease was found to be invasive with sclerosing cholangitis, suggesting a high potential for recurrence. He was referred to medical oncology for follow-up. Mr. WCs past medical history included a history of hypertension, which was managed with diet, exercise (daily walks), and hydrochlorothiazide. He reported a history of a deep venous thrombosis in his left leg secondary to trauma approximately 11 months prior to his diagnosis. He had no known allergies to medications or food. Family history was significant for cardiovascular disease: his father died from cardiac disease, and his mother died from a stroke. The patient was married with three grown children who were alive and well. He lived with his wife who had a limited functional status due to peripheral vascular disease and diabetes mellitus. Social history included pipe and cigar smoking 1-2 times per day for a period of approximately 20 years; he quit 30 years ago. Alcohol intake was rare (approximately 1 can of beer per month). Upon presentation Mr. WC was asymptomatic and in no acute distress. He reported increased fatigue 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 findings within normal limits with the exception of slight edema of the lower extremites bilaterally. The health care team discussed a plan for adjuvant chemotherapy with cisplatin and gemcitabine with the patient and his wife. The infusion nursing staff initiated pretreatment chemotherapy teaching. Assessment of the the patients venous access revealed that he had extremely limited access for the administration of multiple (six) cycles of therapy. The health care team recommended the insertion of a subcutaneous central venous access device. The patient underwent insertion of a port-a-cath in interventional radiology the following week and the first cycle of chemotherapy was initiated. The patient received prehydration with normal saline and antiemetics that included palonosetron, aprepitant, and dexamethasone. In addition, he received antiemetic prescriptions to manage delayed nausea and vomiting. The following laboratory parameters were measured prior to chemotherapy: white blood cell count, 7,200/L; hemoglobin, 13.5 g/dL; hemaotcrit, 42%; platelets, 354,000/L; and creatinine, 1.1 mg/dL. Chemotherapy was administered without consequence. The therapy was well tolerated by the patient. Anticipatory care was reviewed prior to discharge and the patient demonstrated a good understanding of self-care strategies. He was provided with the number for the Nurse Help Line and instructed to call with any questions or problems. Mr. WCs risk for thromboembolic complications included a primary diagnosis of a gastrointestinal malignancy that was treated with both surgery and chemotherapy; in addition, he had a pretreatment platelet count of 354,000/L, a central venous catheter, and a history of a relatively recent thromboembolic event. Although these risks were documented, Mr. WC did not receive thromboprophylaxis. Currently, the prophylactic use of anticoagulants to prevent embolic events in the ambulatory chemotherapy population has not been substantiated by strong evidence generated through randomized clinical trials. The study by Agnelli and colleagues (2009) begins to address this issue and provides some evidence that thromboprophylaxis with the low-molecular-weight heparin nadroparin is effective in reducing thromboembolic events in ambulatory chemotherapy patients who are at greater risk for developing these complications; however, it is important to note that the exclusion criteria included adjuvant chemotherapy and recent (defined as within 3 months) venous or arterial thrombotic events. Therefore, Mr. WC would not have met the eligibility criteria for enrollment. Additional clinical trials are needed before global recommendations about thromboprophylaxis in ambulatory chemotherapy patients at high risk for thrombotic events can be made. Mr. WC completed six cycles of therapy without difficulty. During his last office visit, he was noted to be doing well with no evidence of active disease.

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received nadroparin and 15 (3.9%) of 381 patients who received placebo developed thromboembolic events. Five patients in the nadroparin group experienced a major bleeding event versus none in the placebo group. Major bleeding events were defined as fatal or clinically overt events. The incidence of minor bleeding events was comparable across the treatment groups. The authors concluded that the administration of prophylactic nadroparin in this high-risk population was effective in decreasing the rate of thrombotic complications by approximately 50%. The benefit was most evident in patients with lung and gastrointestinal malignancies.

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). Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. 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). Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 133(6 Suppl):381S453S. Heit JA, Silverstein MD, Mohr DN, et al (2002). Risk factors fro deep vein thrombosis and pulmonary embolism: a population-based case-control study. Archives of Internal Medicine, 160, 809-815. Khorana AA, Francis CW, Culakova E, Lyman GH (2005). Risk factors for chemotherapy associated venous thromboembolism in a prospective observational study. Cancer, 104, 2822-2829. Khorana AA, Kuderer NM, Culakova E, et al (2008). Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood, 211, 4902-4907. Levine MN, Gent M, Hirsh J, et al (1988). The thrombogenic effect of anticancer therapy in women with stage II breast cancer. New England Journal of Medicine, 318, 404-407. Lyman, GH, Khorana AO, Falanga A, et al (2007). American Society of Clinical Oncology Guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. Journal of Clinical Oncology, 25:5490-5505. National Comprehensive Cancer Network (2011). Clinical practice guidelines in oncology: venous thromboembolic disease. Version 2.2011. Accessed from http:// www.nccn.org. Saphner T, Tormey DC, Gray R (1991). Venous and arterial thrombosis in patients who received adjuvant therapy 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 thrombosis and pulmonary embolism: a 25-year population based study. Archives of Internal Medicine, 158, 585-593. l

Patient Education, Support, and Safety

Effective management of patients receiving VTE prophylaxis includes the provision of appropriate safety measures as well as timely 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 therapy. The Joint Commission has identified the provision of detailed information to patients about their medication as a National Patient Safety Goal. Patients and families should be educated on the potential complications of anticoagulant agents. If low-molecularweight heparin is selected for prophylaxis, the patient (or a family member) must be taught how to administer subcutaneous injections. Monitoring plans should also be carefully reviewed.

conclusion
VTE is a common and serious complication in cancer patients undergoing treatment in the ambulatory setting. Clearly, the availability of an empirically validated model to identify appropriate candidates for thromboprophylaxis would be of substantial benefit to practicing clinicians. In addition, more data are needed to identify the optimal method of prophylaxis for patients who are at high risk. Oncology nurses need to be aware of the potential for VTE, be involved in the identification of patients at risk, and keep abreast of emerging data from clinical trials that have the potential to affect practice.

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Reducing the Risk for Recurrent Venous Thromboembolism

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP
University of California, San Francisco

ABSTRACT

Patients with cancer are at increased risk for recurrent VTE compared with patients without a cancer diagnosis. This commentary reviews key findings from the CLOT trial, which evaluated the role of lowmolecular-weight heparin in preventing VTE, and their implications for oncology nursing practice.

enous thromboembolism (VTE) occurs frequently 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 first manifestation of neoplastic disease and is associated with significant morbidity and mortality in patients with cancer. The incidence of VTE observed during autopsy has been reported to be as high as 50% to 60% versus 4% to 20% in patients observed clinically (Lyman et al, 2007; Shen & Pollak, 1980). Patients with cancer who are hospitalized 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 type, chemotherapy and hormonal therapy, surgery 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 therapy in patients with cancer is clinically challenging. Once these patients develop VTE, they are at higher risk for recurrent VTE events compared with patients without a cancer diagnosis (Buller et al, 2004). Historically, 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 unfractionated heparin by intravenous infusion, with therapy lasting 5 to 7 days. This period was followed by vitamin K antagonist therapy with warfarin or a similar agent, adjusted to provide an international normalized ratio (INR) of 2.0 to 3.0, with therapy lasting approximately 3 to 6 months (Buller et al, 2004). Recent data suggest that thromboprophylactic therapy following an initial VTE event in patients with malignancy should be administered indefinitely, or for at least as long as the cancer is active (Zacharski, Prandoni, & Monreal, 2005; Levine, 2002). Additionally, low-molecular-weight heparin is currently preferred as an effective and safe treatment for prophylaxis and management of VTE (Karimi & Cohan, 2010).

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In patients without cancer, warfarin is considered to be the mainstay of therapy for oral anticoagulation but complications can occur with this agent
(Pangilinan, Pangilinan, & Worden, 2007; Zacharski, Prandoni, & Monreal, 2005). The drug is rapidly absorbed with a long half-life of 36 to 42 hours (Hirsh, Fuster, Ansell et al, 2003). Warfarin has a narrow therapeutic

window, and its efficacy can be affected by genetic polymorphisms, dietary intake, and drug-drug interactions 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 considerably expanded.

challenges With Warfarin Therapy as Secondary Prophylaxis

In one community-based trial of patients receiving warfarin for a variety 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 malignancy (Rose et al, 2007). The rate of complications can be higher in patients with cancer who receive warfarin therapy. An increased incidence of bleeding has been demonstrated in several studies (Zacharski, Prandoni, & Monreal, 2005). Risk factors such as duration of therapy, recent surgeries or trauma, older age (>65 years), and renal or hepatic dysfunction may contribute to the increased risk for bleeding (Zacharski, Prandoni, & Monreal, 2005). The therapeutic window can be difficult to achieve in patients with cancer, as patients may require interruptions of therapy due to the need for procedures or because they experience treatment-related thrombocytopenia (Falanga & Zacharski, 2005). Patients with cancer may experience recurrent thrombosis despite treatment with warfarin because of changes in nutritional status, drug interactions, and alterations in liver metabolism, which may result from the cancer or its treatment (Falanga & Zacharski, 2005). Because of these factors, improvements in anticoagulation for patients with cancer are needed. Secondary prophylaxis with LMWH offers an alternative method of anticoagulation.

The Significance of the clOT Study

The CLOT (Comparison of Low molecular weight heparin versus Oral anticoagulant Therapy) study was the first large-scale trial to compare the safety

and efficacy of LMWH and warfarin therapy in the prevention of recurrent VTE in patients with cancer (Lee et al, 2003) (Table 1). This pivotal trial demonstrated that the risk for symptomatic, recurrent thromboembolism in patients with cancer was significantly reduced with the administration of dalteparin LMWH compared with traditional oral anticoagulant therapy with warfarin (Lee et al, 2003). Study participants were patients with cancer who had acute, symptomatic proximal deep vein thrombosis (DVT), pulmonary embolism (PE), or both. Patients were randomly assigned to either LMWH (dalteparin) at a dose of 200 IU per kg of body weight subcutaneously once daily for 5 to 7 days and a coumarin derivative (warfarin or acenocoumarol) for 6 months (target INR, 2.5) or dalteparin alone for 6 months (200 IU per kg once daily for 1 month, followed by a daily dose of approximately 150 IU per kg for 5 months). Intensive anticoagulation was provided at the start of the regimen followed by a reduced-dose therapy, with the goal of reducing the risks (eg, bleeding) of anticoagulant therapy in this patient population. The results of the study showed: During the 6-month study period, 27 of 336 patients in the dalteparin group experienced recurrent VTE versus 53 of 336 patients in the oral anticoagulant therapy group (hazard ratio, 0.48; P=0.002) The probability of recurrent thromboembolism at 6 months hazard ratio: hazard ratios was 17% in the oral anticoagare often used to measure ulant therapy group compared survival at any point in time in with 9% in the dalteparin group a group of patients who have No significant differences were been given a specific treatnoted between the daltepament compared with a control rin group and the oral anticogroup given another treatment agulant group in rate of major or placebo. A hazard ratio of bleeding (6% vs 4%, respec1.0 means that there is no diftively) or any bleeding (14% vs ference in survival between the 19%, respectively) two groups. A hazard ratio of The mortality rate in the daltepagreater than 1 or less than 1 rin group at 6 months was 39% means that survival was better compared with 41% in the oral in one of the groups. anticoagulant therapy group The P value for the number of recurrent VTE events indicated that the results of the study were significant (Table 2). Strengths of this study included the randomized controlled trial design, which is considered the gold standard in clinical research, and the evenly

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

STudy auThORS meyer et al, 2002

CANTHANOX Study

STudy deSign

ReSulTS

imPlicaTiOnS

Open-label, multicenter, randomized trial involving 146 cancer patients receiving either enoxaparin LMWH or warfarin for 3 months

Of 71 evaluable patients receiving warfarin, 15 (21.1%) experienced one major outcome event vs 7 (10.5%) in the study arm. A total of 6 deaths occurred from hemorrhage in the warfarin group vs 0 in the LMWH group; 17 deaths occurred in the warfarin group vs 8 in the LMWH group.

Warfarin in cancer patients who develop a VTE is associated with a high bleeding rate; LMWH may be as effective as oral anticoagulants and may be safer. Larger studies are needed to confirm findings.

lee et al, 2003

CLOT Study Open-label, multicenter, randomized trial involving 676 cancer patients assigned to dalteparin 200 U/kg followed by maintenance LMWH 150 U/kg (treatment time, 6 mo) or dalteparin followed by oral anticoagulation Follow-up at end of study period of 6 months showed that 27 of 336 patients in the dalteparin group had recurrent VTE vs 53 of 336 patients in oral anticoagulant group (HR, 0.48; 95% CI, 0.30-0.77; P=0.002) Patients receiving dalteparin initially followed by maintenance LMWH had lower recurrence rates of VTE, although rates of bleeding and death at 6 months were not significantly different between the two groups

hull et al, 2006

LITE Study Open-label, multicenter, randomized trial with 200 patients receiving either tinzaparin LMWH or vitamin-K antagonist therapy for 3 months; outcomes were assessed 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, -21.710.7); minor bleeding (27%) occurred in the LMWH group versus 24% in the control group (95% CI, -9.1-15.1). Major bleeding occurred in 0% of the LMWH group compared with 2.1% in the control group; mortality was equal for both (47%). The P value was not significant at 3 months, but was 0.44 at 1 year; the authors concluded that their findings confirm the limited existing data indicating LMWH is more effective than vitamin K antagonist therapy for the prevention of VTE in cancer patients; mortality was not affected.

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

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balanced study groups. Limitations included its open-label versus blinded design, which could have introduced bias into the results. In addition, the manufacturer of the study drug, dalteparin, was the sponsor. However, as the authors indicated, a double-blinded study design could have been unsafe for patients who had comorbid conditions and were taking multiple concomitant agents potentially increasing their risk for drug interactions (Lee et al, The results demonstrated that the study drug essentially cut in half the risk for recurrent thromboembolism compared with the conventional therapy of LMWH followed by oral anticoagulant therapy. In addition, the new therapy did not increase the risk for bleeding (although the two groups had virtually the same amount of bleeding). At 6 months 130 patients (39%) died in the
2003).

dalteparin group versus 136 (41%) in the oral anticoagulant therapy group. Progressive cancer was the cause of death for 90% of the deaths in both groups (Lee et al, 2003).

conclusion
Based on data from the pivotal trials examining the efficacy of LMWH compared with oral anticoagulant therapy, National Comprehensive Cancer Network guidelines recommend LMWH (dalteparin, enoxaparin, tinzaparin), fondaparinux, or unfractionated heparin as initial treatment for VTE; LMWH is also recommended as the preferred treatment for chronic management of VTE for the first 6 months as monotherapy without warfarin in patients with proximal VTE or PE and the prevention of

Table 2. Understanding Statistical Analysis Via the CLOT Study

STudy Value P Value

deScRiPTiOn
Statistical inference requires beginning with the hypothesis that there is no difference between a treatment group and a control group. The P value helps us calculate the probability that the difference demonstrated in a study occurred because of chance. Statistical significance usually requires a P value of 0.05 or less. 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 indicates increased risk rate; HR <1.0 indicates decreased risk rate. A range around a measurement that demonstrates how precise the measurement is.

examPle FROm The clOT STudy

27 of 336 patients in the dalteparin group had recurrent VTE versus 53 of 336 patients in the oral anticoagulant therapy group (HR, 0.48; P=0.002). This P value indicates that there is 0.002 chance that the results in the trial occurred by chance and thus is a significant finding.

hazard ratio

Measuring the difference between the study group and the control group in the CLOT study, the HR was 0.48. This indicates that the risk was decreased for the study group (a 52% reduction in the risk for recurrent VTE) compared with the warfarin group, a significant finding of the investigation. In examining the probability of symptomatic VTE in patients with cancer, the HR was 0.48 with a 95% CI. If the CI had been a very wide range, the data would not be considered as significant. With a 95% CI, there is a 5% chance that the results are incorrect.

confidence interval

Based on information from Norman et al, 2009. VTE = venous thromboembolism; HR = hazard ratio; CI = confidence interval. www.i3Health.com Oncology Data Advisor
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recurrent VTE in patients with advanced or metastatic cancer (NCCN, 2010). The minimum recommended duration of anticoagulation therapy is 3 to 6 months for VTE and 12 months for PE; indefinite anticoagulation is recommended for patients with active cancer or persistent risk factors (NCCN, 2011). The American Society of Clinical Oncology and the European Society for Medical Oncology have developed similar guidelines incorporating LMWH as well (Khorana, 2009; Patients with cancer are at risk for VTE due to a myriad of factors, including active disease and chemotherapy treatment. Oral anticoagulants such as warfarin have been used to treat VTE in patients with cancer; however, achieving and maintaining therapeutic INRs in this population is inherently difficult as underanticoagulation and supratherapeutic results are common (Table 3) (Hull et al, 2006; Meyer et al, 2002). LMWH has demonstrated efficacy and safety in the treatment of cancer patients who develop VTE. Additional trials are needed to continue to define the role of LMWH and the benefits of therapy in this population.
Lyman et al, 2007).

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 production of this manuscript.

REFERENCES
Falanga A & Zacharski L. (2005). Deep vein thrombosis 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 Cardiology Foundation guide to warfarin therapy. Circulation, 107, 1692-1711. Hull RD, Pineo GF, Brant RF, et al; LITE Trial Investigators (2006). Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. The American Journal of Medicine, 119 (12), 1062-1072. Khorana AA (2009). Cancer and thrombosis: implications 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

Table 3. LMWH vs Vitamin K Antagonists

lmWh dosing
Body weight-adjusted dose; no need for laboratory monitoring. Given as subcutaneous injection.

Vkas
Titrated dose to achieve therapeutic INR (most commonly 2.03.0) Oral administration

expected response

Predictable anticoagulant response with rapid bioavailability after injection; twice daily or once daily formulations available Therapeutic response not affected by concomitant medications or diet

Dose must be adjusted frequently in most patients to achieve INR

Potential for drug-drug interactions

Drug-drug and drug-diet interactions common with VKAs

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

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C A S E STU D y: Patient With Metastatic Colorectal Cancer

Mr. Santos was a 56-year-old man with a diagnosis of metastatic colorectal cancer to the liver. He was started on FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy after the placement of an indwelling vascular access device. His baseline performance status was poor, with a Karnofsky rating of 70. The patient was receiving multiple medications for comorbid conditions. Mr. Santos had few caregivers to assist him at home and relied on friends to bring him to treatment. One friend reported that Mr. Santos activity level was very low, with much of his time spent lying down or resting, and diet very poor. Although this friend encouraged him to be more active, Mr. Santos had difficulty walking even short distances because he often felt very fatigued 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 of left leg pain and swelling. After assessment and physical examination by the oncology nurse practitioner, he underwent Doppler ultrasonography of his left leg to rule out lower extremity VTE. Test results were positive, leading to a diagnosis of a large near-occlusive popliteal VTE. After discussion with Mr. Santos and his friend, the health care team initiated treatment for the VTE with LMWH followed by maintenance LMWH. With his active cancer (indicated by his metastatic disease), the health care team felt Mr. Santos would have a reduced risk for VTE recurrence with LMWH. Adherence to oral anticoagulation therapy and the potential for drug interactions were also considerations in the treatment planning. Mr. Santos was receiving a 5-fluorouracilbased regimen, which had the potential to interact with oral warfarin (Khorana, 2009). Key factors in the therapeutic decision-making process included the fact that Mr. Santos agreed to learn self-injection techniques with the aid of his friend, who had decided to move in with him and act as a caregiver. In addition, Mr. Santos neuropathy symptoms precipitated a change to irinotecan-based chemotherapy with FOLFIRI and the adjustment of his antiemetics to improve control of his nausea.

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: efficacy and safety of antithrombotic treatment options in patients with cancer. Cancer Treatment Reviews, 28, 145-149. Linkins L-A (2008). Management of venous thromboembolism in patients with cancer: role of dalteparin. Vascular Health and Risk Management, 4 (2), 279-287. Lyman GH, Khorana AA, Falanga A, et al (2007). American Society of Clinical Oncology Guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. Journal of Clinical Oncology, 25, 55490-5505. doi:10.1200/ JCO.2007.14.1283 Meyer G, Marjanovic Z, Valcke J, et al (2002). Comparison of low-molecular-weight heparin and warfarin for the secondary 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). Clinical practice guidelines in oncology: venous thromboembolic 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), 284286. Accessed from http://www.comunityoncology.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). Effectiveness of warfarin among patients with cancer. Journal of General Internal Medicine, 22 (7), 997-1002. doi:10.1007/s11606-007-0228-y Zarcharski LR, Prandoni P, & Monreal (2005). Warfarin versus low-molecular-weight-heparin therapy in cancer patients. The Oncologist, 10, 72-79. l

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