Oncology Data Advisor: Prophylaxis of Venous Thromboembolism in The Outpatient Setting
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DAT TA A DVI SO R O N C O L O G Y DA
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Interpreting the Science Behind Evidence-Based Cancer Care www.i3Health.com www.i3Health .com
Volume Volum e 1 Number 1
Props of Vos Trobobos t Otptt Stt NALYSES YSES EXPE RT A NAL
Identifying Patients Who May Bt Fro Troboprops Regina S. Cunningham, PhD, RN, AOCN®
Mount Sinai Medical Center
R t Rs for Rrrt Vos V os Trobob Trobobos os Pamela Hallquist Viale, RN, MS, CS, ANP, ANP, AOCNP®
University of California, San Francisco
Release date: June date: June 15, 2011 Expiration date: June date: June 14, 2012 Educational credit: 1.0 credit: 1.0 contact hour Estimated time to complete activity: 60 activity: 60 minutes
This activity is supported by an independent educational grant from Eisai Eisai Inc. © 2011 i3 Health. All rights reserved.
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Target Audience
Commercial Support
Oncology nurses and other members of the multidisciplinary cancer care team involved in the prophylaxis and management of venous thromboembolism (VTE).
This activity is supported by an independent educational grant from Eisai, Inc.
Disclosure of Conflicts of Interest Acti vity Ove Overvi rview ew VTE occurs frequently in patients with cancer and is considered one of the leading causes of death in this population. This CEcertied 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 benet from thromboprophlaxis. SeSe 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 key study ndings 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 3. cancer Describe clinical trial data evaluating the safety and efcacy of anticoagulant therapy in patients with cancer 4. Explain how the “P “P value,” value,” “condence interval,” and “hazard ratio” can validate clinical trial study results
Faculty Regina S. Cunningham, PhD, RN, AOCN ® (Chairperson) Mount Sinai Medical Center Pamela Hallquist Viale, Vi ale, RN, MS, CS, ANP, ANP, AOCNP® University of California, San Francisco
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EXPERT AN AL ALYSIS YSIS
I P W M B F T Regina S. Cunningham, PhD, RN, AOCN ® Mount Sinai Medical Center
ABS TRA TRACT CT
Understanding VE risk is the first step in identiying cancer patients who may benefit rom prophylaxis early, beore serious or lie-threatening consequences consequen ces maniest. Tis brie analysis reviews a VE risk prediction model developed by Khorana and colleagues and its application in the ambulatory chemotherapy setting.
V
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 identication 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. UnderU nderstanding risk is the rst step in identifying patients who may benet from prophylaxis early, before sese rious 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.
U U R 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
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EXPERT ANA LYSIS
for thromboembolic complications (Khorana et al, 2004).
D R
make any recommendations on the use of antithrombotic prophylaxis in patients receiving chemotherapy in the ambulatory setting (Lyman et al, 2007; Geerts et al, 2008).
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 assist practicing clinicians in proactively identifying patients for whom thromboprophylaxis may be of most value. Studies have demonstrated clear benet 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 am-
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
bulatory there are limited effective strategiessetting, to systematically identifydata and on 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
tissue disorders. Patients were followed prospectively for a maximum of four cycles of therapy. therapy. Sixty patients (2.2%) developed VTE in the derivation cohort. The variables that were found to be sttst st associated with the development of symp-
Table T able 1. Predictors of VTE
sttst st: describes a math-
P M
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.
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ematical measure of difference between groups. The difference is i s said to be statistically statistic ally signicant if it is greater than what might be expected to happen by chance alone 95% of the time. Although statistically signicant usually refers to 95% concon dence, sometimes other condence levels such as 99% or 90% are specied. 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 signicance. Risk varied by cancan cer 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 l
EXPERT AN AL ALYSIS YSIS
Table T able 2. Criteria for VTE Prediction Model
incluSiOn cRiTeRia
excluSiOn cRiTeRia
Histologically conrmed diagnosis of cancer
Receiving concurrent cytotoxic, biologic, or immunologic therapy for another condition
Initiating new chemotherapy regimen
Continuous single-agent therapy
Anticipated to complete four cycles of therapy
Diagnosis of acute leukemia
18 years of age or older
Pregnant or lactating
Able to provide informed consent
Active infection requiring treatment
Currently participating in a double-blind study
Status post-stem cell transplant 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 derivatio derivation n 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
receiving chemotherapy. Patients with lung, gastrointestinal (stomach, colon, rectum), pancreatic, breast, ovarian, or head and neck cancer were recruited from 62 centers. Patients with a recent history of thrombotic events, an Eastern Cooperative Oncology Group performance status score >2,
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.
any active bleeding, thrombocytopenia, an elevated activated partial thromboplastin time ratio, active ulcer disease, cerebral metastases, severe hypertension, renal or liver insufciency, 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 rst 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
T T H-R A P A more recent study used some of the variables identied by Kohrona and colleagues to select amambulatory 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 benet of nadroparin in reducing the inci dence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer www.i3Health.com Oncology Data Advisor l
c (oor) sttst: a measure of how well a clinical prediction rule can correctly rank-order patients by risk. A model that accurately discriminates patients 85% of the time would have a C statistic of 0.85; with completely random predictions, as in a coin toss, the C statistic would be 0.5; and a model that discriminates perfectly between patients with and without events would have a C statistic of 1.0.
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EXPERT ANA LYSIS
CASE STUDY:
Patient With Cholangiocarcinoma
Mr. WC was a 74-year-old man who initially presented with abdominal pain, mild itching, and elevated liver unction tests. Afer a complete workup, he was diagnosed with cholangiocarcinoma. He underwent a surgical resection o the bile ducts. Te disease was ound to be invasive with sclerosing cholangitis, suggesting a high potential 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
normal limits with the exception o slight edema o the lower extremites bilaterally. Te health care team discussed a plan or adjuvant chemotherapy with cisplatin and gemcitabine with the patient and his wie. Te inusion nursing staff initiated pretreatment chemotherapy teaching. Assessment o the the patient’s venous access revealed that he had extremely limited access or the administration o multiple (six) cycles o therapy. Te health care team recommended the insertion o a subcutaneous central venous access device. Te patient underwent insertion o a port-a-cath in interven-
thrombosis in his lef leg secondary to trauma approximately 11 months prior to his diagnosis. He had no known allergies to medications or ood. Family history was significant or cardio vascular disease: his ather died rom cardiac disease, and his mother died rom a stroke. Te patient was married with three grown children who were alive and well. He lived with his wie who had a limited unctional status due to peripheral vascular disease and diabetes mellitus. Social history included pipe and cigar smoking 1-2 times per day or a period o approximately 20 years; he quit 30 years ago. Alcohol intake was rare (approximately 1 can o beer per month). Upon presentation Mr. WC was asymptomatic 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
tional radiology the ollowing week colleagues (2009) begins to address and the first cycle o chemotherapy this issue and provides some eviwas initiated. Te patient received pre- dence that thromboprophylaxis with hydration with normal saline and an- the low-molecular-weight heparin tiemetics that included palonosetron, nadroparin is effective in reducing aprepitant, and dexamethasone. In thromboembolic events in ambulaaddition, he received antiemetic pre- tory chemotherapy patients who are scriptions to manage delayed nausea at greater risk or developing these and vomiting. Te ollowing laborato- complications; however, it is imporry parameters were measured prior to tant to note that the exclusion criteria chemotherapy: chemothe rapy: white blood cell count, included adjuvant chemotherapy and 7,200/µL; hemoglobin, 13.5 g/dL; he- recent (defined as within 3 months) maotcrit, 42%; platelets, 354,000/µL; venous or arterial ar terial thrombotic t hrombotic events. and creatinine, 1.1 mg/dL. Tereore, Mr. WC would not have Chemotherapy was administered met the eligibility criteria or enrollwithout consequence. Te therapy ment. Additional clinical trials are was well tolerated by the patient. An- needed beore global recommendaticipatory care was reviewed prior to tions about thromboprophylaxis in discharge and the patient demonstrat- ambulatory chemotherapy patients at ed a good understanding o sel-care high risk or thrombotic events can strategies. He was provided with the be made. number or the Nurse Help Line and Mr. WC completed six cycles o instructed to call with any questions therapy without difficulty. During or problems. his last office visit, he was noted to be Mr. WC’s WC’s risk or thromboembol- doing well with no evidence o active
examination revealed findings within
ic complications included a primary
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diagnosis o a gastrointestinal malignancy that was treated with both surgery and chemotherapy; in addition, he had a pretreatment platelet count o 354,000/µL, a central venous catheter, and a history o a relatively recent thromboembolic event. Although these risks were documented, Mr. WC did not receive thromboprophylaxis. Currently, the prophylactic use o anticoagulants to prevent embolic events in the ambulatory chemotherapy population has not been substantiated by strong evidence generated through randomized clinical trials. Te study by Agnelli and
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 dened 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 benet was most evident in patients with lung and gastrointestinal malignancies.
P E, E , S, S 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 identied 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.
C VTE is a comm common on and seri serious ous comp complica lica tion 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 benet to practicing clinicians. In adad dition, 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 identication of patients at risk, and keep abreast of emerging data from clinica l trials that have the potential to affect practice.
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D Regina S. Cunningham, PhD, RN, AOCN ® has nothing to disclose. No writing assistance was utilized in the production of this manuscript.
REFERENCES Agnelli G, Gusso ni 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, Nursing, 21, 21, 21-40. Geerts WH, Bergqvist D, Pineo GF, et al (2008). Prevention of venous thromboembo thromboembolism: lism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 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. 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, Cancer, 104, 104, 2822-2829. Khorana AA, Kuderer NM, Culakova E, et al (2008). Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood, 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, Medicine, 318, 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 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 f rom 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 cancer. Journal of Clinical Oncology, Oncology, 9, 286-294. Silverstein MD, Heit JA, Mohr DN, et al (1998). Trends in the incidence of deep vein thrombo Trends sis and pulmonary embolism: a 25-year population based study. Archives of Internal Medicine, Medicine, 158, l 585-593.
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EXPERT ANA LYSIS
R R R V T Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP ® University of California, San Francisco
ABS TRA TRACT CT
Patients with cancer are at increased risk or recurrent VE compar Patients compared ed with patients without a cancer diagnosis. Tis commentary reviews key findings rom the CLO trial, which evaluated the role o lowmolecular-weightt heparin in preventing VE, and their implications molecular-weigh or oncology nursing practice.
V
S P
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 rst manifestation of neoplastic disease and is associated with signicant 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
Antithrombotic therapy in patients with cancer is clinically challenging. Once these patients develop VTE, they are at higher risk for recurrent 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 thera-
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.
py 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 last ing 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 indenitely, 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
In one community-based trial of patients receiving warfarin for a variety of reasons, patients with active cancer
and efcacy 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 signicantly reduced with the administration of daltedalteparin 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 daltepari n 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
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, 200 2007). 7). 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 difcult to achieve in papa tients with cancer, as patients may require interruptions of therapy due to the need for procedures or because
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 (zr rto, rto, 0.48; P=0.002) • The probability of recurrent thromboembolism at 6 months zr rto: 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 signicant differences differences were
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 & Zachar Zac harski ski, 200 2005). 5). Because of these factors, improvements in anticoagulation for patients with cancer are needed. Secondary prophylaxis with LMWH offers an alternative method of anticoagulation.
noted between the daltepabeen given a specic treattreat ment 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 morta mortality lity rate in the the daltepa daltepa-greater 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 signicant (Table 2). Strengths of this study included the randomized controlled trial design, which is considered the gold standard in clinical research, and the evenly
(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 efcacy 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, Pangilinan, & Worden, 2007; Zacharski, Zacharski, Prandoni, Prandoni, & Monreal, 2005). In patients with cancer, the scope of
complications is considerably expanded.
C W W T S P
T S CLOT S The CLOT (Comparison of Low molecular weight heparin versus Oral anticoagulant Therapy) study was the rst large-scale trial to compare the safety
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EXPERT ANA LYSIS
Table T able 1. LMWH vs Oral Anticoagulant Therapy in the Prevention of VTE Recurrence
STudy auThORS
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 conrm ndings.
Open-label, mu multicenter, ra 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) =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 signicantly different between the two groups
Open-label, mu multicenter, ra randomized trial with 200 papatients receiving either tinzatinzaparin 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 (P =0.44; =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 signisignicant at 3 months, but was 0.44 at 1 year; the authors concluded that their ndings conrm the limited existexisting data indicating LMWH is more effective than vitamin K antagonist therapy for the prevention of VTE in cancer patients; mortality was not affected.
mr t , 2002 CANTHANOX Study
l t , 2003 CLOT Study
h t , 2006 LITE Study
LMWH = low-molecular-weight heparin; VTE = venous thromboembolism; HR = hazard ratio; CI = condence interval.
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EXPERT AN AL ALYSIS YSIS
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, 2003).
The result s demo demonstra nstrated ted 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
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).
C 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 T able 2. Understanding Statistical Analysis Via the CLOT Study
STudy Value V P V
hzr rto
co trv
deScRiPTiOn
examPle FROm The clOT STudy
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 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 therapy group (HR, 0.48; P =0.002). =0.002). This P value value indicates that there is 0.002 chance that the results in the trial occurred by chance and thus is a signicant nding.
Refers to the rate at which events happen; the HR is an expression of the hazard or
Measuring the difference between the study group and the control group in the CLOT
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.
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 signicant nding of the investigation.
A range around a measurement that demonstrates how precise the measurement is.
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 signicant. With a 95% CI, there is a 5% chance that the results are incorrect.
Based on information from Norman et al, 2009. VTE = venous thromboembolism; HR = hazard ratio; CI = condence interval.
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EXPERT ANA LYSIS
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; Lyman et al, 2007).
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 pati ents with canc er; howe ver, achi evin g and maintaining therapeutic INRs in this population is inherently difficult as underanticoagulat underanticoagulation ion 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.
D Pamela Hallquist Viale, Viale , RN, MS, CS, ANP ANP,, AOCNP®, discloses relationships with Merck (speaker), Amgen (speaker), (sp eaker), and Novartis Novar tis (speaker). (spe aker). 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 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 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, Medicine, 119 (12), 1062-1072. Khorana AA (2009). Cancer and thrombosis: implications of published guidelines for clinical practice. Annals of Oncology Oncology,, 20, 1619-1630. doi:10.1093/ annonc/mdp068 Lee AYY, Levine MN, Baker RI, et al (2003). Low-molecular
Table T able 3. LMWH vs Vitamin K Antagonists
dos
lmWh
Vkas
Body weight-adjusted dose; no need for laboratory monitoring. Given as subcutaneous injection.
Titrated dose to achieve therapeutic INR (most commonly 2.03.0) Oral administration
ept rspos
Predictable anticoagulant response with rapid bioavailability after injection; twice daily or once daily formulations available
Dose must be adjusted frequently in most patients to achieve INR
Pott for r-r trtos
Therapeutic response not affected by concomitant medications or diet
Drug-drug and drug-diet interactions common with VKAs
Based on information from Falanga & Zarcharski, 2005. VKAs = vitamin K antagonists; INR = International Normalized Ratio. 12
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CASE STUDY STUDY:: Patient With Metastatic Colorectal Cancer Mr. Santos was a 56-year-old man with a diagnosis o metastatic colorec-
because he ofen elt very atigued and had nausea and mild-to-moderate
would have a reduced risk or VE recurrence with LMWH. Adherence to
tal cancer to the liver. He was started on FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy afer the placement o an indwelling vascular access device. His baseli baseline ne perormance status was poor, with a Karnosky rating o 70. Te patient was receiving multiple medications or comorbid conditions. Mr. Santos had ew caregivers to assist him at home and relied on riends to bring him to treatment. One riend reported
neuropathy symptoms related to his oxaliplatin therapy. At his third visit to the clinic, Mr. Santos arrived in a wheelchair with new complaints o lef leg pain and swelling. Afer assessment and physical examination by the oncology nurse practitioner, he underwent Doppler ultrasonography o his lef leg to rule out lower extremity VE. est results were positive, leading to a diagnosis o a large near-occlusive popliteal VE. Afer discussion with
oral anticoagulation therapy and the potential or drug interactions were also considerations in the treatment planning. Mr. Santos was receiving a 5-fluorouracil–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. Santos agreed to learn sel-injection techniques with the aid o his riend, who had decided to move in with him and
that activity level was lying very low, Mr. withSantos’ much o his time spent down or resting, and diet very poor. Although this riend encouraged him to be more active, Mr. Santos had dificulty walking even short distances
Mr. and his treatment riend, theor health care Santos team initiated the VE with LMWH ollowed by maintenance LMWH. With his active cancer (indicated by his metastatic disease), the health care team elt Mr. Santos
act a caregiver. In addition, Mr. Santos’as neuropathy symptoms precipitated a change to irinotecan-based chemotherapy with FOLFIRI and the adjustment o his antiemetics to improve control o 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 diseasein the cancer patients: efcacythromboembolic and safety of antithromantithrom botic 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). ( 2007). American Society of Clinical Oncology Guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. Journal of Clinical Oncology, 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
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in patients with cancer: a randomized controlled study. 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 f rom http:// www.nccn.org. Norman, GR & Steiner DL. (2009). P less than 0.05: statistical inference. Community Oncology, 6 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). EffecEffectiveness of warfarin among patients with cancer. Jourcancer. Jour nal of General Internal Medicine, Medicine, 22 (7), 997-1002. doi:10.1007/s11606-007-0228-y Zarcharski LR, Prandoni P, & Monreal (2005). Warfarin versus low-molecular-weight-heparin low-molecular-weight-heparin therapy in cancer l patients. The Oncologist, 10, 72-79.
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