靜脈血栓栓塞症於癌症病人之流行病學與治療現況

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國立臺灣大學醫學院臨床藥學研究所碩士論文

Graduate Institute of Clinical Pharmacy College of Medicine

National Taiwan University Master Thesis

靜脈血栓栓塞症於癌症病人之流行病學與治療現況 Epidemiology and Clinical Profile of Venous

Thromboembolism in Cancer Patients

周丹薇 Tan-Wei Chew

指導教授：蕭斐元博士高純琇博士

Advisor: Fei-Yuan Sharon Hsiao, Ph.D.

Churn-Shiouh Gau, Ph.D.

中華民國 101 年 7 月

July, 2012

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謝辭

兩年的臨藥所生活就這樣過去了，到現在還是覺得有點難以置信，過去常常說很累很煩不想寫論文的研究生生活現在倒開始懷念起來了。

能安然地渡過這兩年，要感謝的人實在太多了。感謝凍齡美鵲娘－蕭斐元老師花了那麼多心力和時間指導我們，不管在學術上還是生活上老師都不遺餘力地給予我們支持與幫助，在我們徬徨無助時幫我們導向正途。老師當新手媽媽已經夠忙了，還要照顧我們這兩個天然呆的學生，真的辛苦了。感謝高純琇老師在忙碌的業務之餘，還給予我研究方法上的指導，讓我的論文架構與分析結果更加全面。如果沒有老師當初的建議，我現在就要擔心我的結果是不是就沒有甚麼發表的價值了。感謝溫有汶老師在背後的支持，讓我可以無後顧之憂地專注於研究上。

感謝沈麗娟老師抽空來參加我的論文口試，提點我在研究上應該注意的關鍵與盲點。感謝老師們的建議與指導，讓我可以順利地完成我的碩士研究。

感謝我的最佳夥伴林婉婷，你真的太重要了！當初你在和信抄病歷的時候，

我一個人在 1222 每天都在期待你抄完病歷回來台大。在寫論文的過程中，因為有你在身邊一起努力，我才能靜下心來繼續奮鬥。謝謝妳常常聽我 murmur 有的沒的，

跟我分享生活中的大小事，當我遇到瓶頸時總是放下手邊的事情來幫助我。感謝小喵總是讓我們隨 call 隨問，還提醒了我們很多論文與口試中需要注意的事項，

即使你在被期中報告轟炸的時候還擠出時間幫我們審稿和 rehearsal，真的太感謝你了。也要感謝新加入天然呆家族的欣諄，在口試前夕給了我們很多寶貴的意見，

還請我們吃好吃的手工餅乾，陪我們渡過口試前的焦慮期。

感謝同窗兩年的阿邵、笑點、阿穴、小花、品慧、Joke、以雯和小餅乾，真的很開心可以跟你們成為同學。跟你們一起吃飯、講垃圾話、看電視、旅遊的時光是我研究所中珍貴的回憶，也是這之中最重要的調劑！因為有你們在，我的研究生生活在苦悶之餘也能充滿歡笑。記得欣諄也說過我們在口試前還能嘻嘻哈哈的真的蠻難得的。感謝經常幫我們處理大小事務的翊吟。謝謝你們所有人這麼照顧常常犯呆的我，我會很想念你們的！真的很感謝你們在我離開前送我的卡片，我看到後來感動地都快哭了，我會把它當作寶貝好好珍惜的。最後也要感謝我的家人和權峰，謝謝你們在這段時間給我的支持和鼓勵，這是我繼續努力下去的動力。

短短兩年的臨藥所生活真的是充滿了苦痛與歡笑，雖然一開始在台北生活真的很不習慣覺得很寂寞，但是我很慶幸自己可以成為臨藥所的一員，認識這麼棒的你們。謝謝你們！

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中文摘要

研究背景靜脈血栓栓塞症(venous thromboembolism)對癌症病人的死亡率和疾病狀況的顯著影響，已是重要的臨床的問題。以往的研究顯示，不同種族的靜脈血栓栓塞症發生率不同。雖然在西方國家對靜脈血栓栓塞症的預防已有完整的治療指引可遵循，但是在亞洲國家，有關靜脈血栓栓塞症的流行病學資料卻仍然有限。

研究目的本群體觀察性研究(population-based observational study)的目的乃為建立臺灣癌症病人發生靜脈血栓栓塞症的流行病學資料，分析發生靜脈血栓栓塞症的危險因子，並探討其臨床特徵和目前國內的治療現況。

研究方法本研究以臺灣健保資料庫 2000 年、2005 年和 2010 年三套百萬人承保抽樣歸人檔為資料來源，找出 2001 年至 2008 年住院主診斷為癌症的新診斷癌症病人，並以初次住院主診斷為癌症的入院日期為 index date。在 index date 的住院主診斷有兩個(含)以上的癌症的病人，則被排除在研究之外。本研究的研究終點為 index date 當天或之後因靜脈血栓栓塞症而住院。本研究共有兩個靜脈血栓栓塞症的定義：定義一為住院檔中出現靜脈血栓栓塞症的診斷，定義二則為住院檔中同時有靜脈血栓栓塞症診斷及靜脈血栓栓塞症的治療。本研究針對所有癌症病人和不同癌症部位的靜脈血栓栓塞症的發生率，及針對發生靜脈血栓栓塞症和沒有發生靜脈血栓栓塞症的病人在年齡、性別、共病症和可能危險因子，連續變項使用 t-test，類別分項使用 Chi-square 或 Fisher’s exact test 進行分析。針對以定義二而住院的病人，則使用邏輯迴歸模型(logistic regression model)進行分析，找出發生靜脈血栓栓塞症的危險因子，並探討靜脈血栓栓塞症長期治療的狀況、復發率與發生出血性副作用的機率。

研究結果在 43,855 名新診斷癌症病人中，1388 名(3.2%) (定義一)和 473 名(1.1%) (定義二)病人在 index date 當天或之後因靜脈血栓栓塞症而入院。靜脈血栓栓塞症的發生率分別為 9.9 每 1,000 人年(1.0 – 68.2 每 1,000 人年) (定義一)和 3.4 每 1,000 人年(0.0 – 16.1 每 1,000 人年) (定義二)。靜脈血栓栓塞症發生率較高的癌症包括：

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肝臟、胰臟、肺臟、多發性骨髓瘤(multiple myeloma)、肉瘤(sarcoma)和非何杰金氏淋巴瘤(non-Hodgkin’s lymphoma)。靜脈血栓栓塞症(定義一)在 index date 30 天、

90 天、180 天和 365 天內的累積發生率(cumulative occurrence)分別為 42.9%、53.5%、

61.7%和 70.8%。靜脈血栓栓塞症(定義二)在 index date 30 天、90 天、180 天和 365 天內的累積發生率分別為 25.2%、39.8%、47.8%和 59.4%。靜脈血栓栓塞症的顯著危險因子包括癌症部位、之前有發生靜脈血栓栓塞症的病史、動脈栓塞症(arterial embolism)、肥胖(obesity)、高血壓、風濕性疾病、接受化學治療、合併治療和胸腔、

腹部或泌尿生殖道大手術。三個月內的輸血治療與靜脈血栓栓塞症風險的降低有關。在 1,388 位因靜脈血栓栓塞症(定義一)住院的病人中，只有 33.6%的病人(n=467) 在當次住院中有接受抗凝血劑的治療或接受栓塞切除術。在 473 位因靜脈血栓栓塞症(定義二)住院的病人中，1.5%的病人(n=7)接受栓塞切除術，其他病人則接受肝素(heparin)或低分子量肝素(low molecular weight heparin)作為靜脈血栓栓塞症的初期治療。81 個病人(19.5%)在第一次靜脈血栓栓塞症後有復發現象。在 415 個存活病人中，266 個病人(64.1%)有接受靜脈血栓栓塞症的長期治療，其中 72.2%的病人(n=192)接受 warfarin 作為長期治療靜脈血栓栓塞症的藥物。長期治療的時間長度中位數為 66 天，其中大約三分之二(58.7%, n=156)的病人的治療時間長度小於或等於 3 個月。

結論雖然臺灣的癌症相關靜脈血栓栓塞症的發生率比高加索族群的發生率來的低，但其發生率比一般亞洲族群(general population)要高得多，尤其是在特定的癌症如：多發性骨髓瘤、胰臟癌、肝癌和肺癌。大部分的靜脈血栓栓塞症發生在癌症新診斷後一年內。在臺灣，目前的治療現狀與國外的臨床治療指引並不一致。

靜脈血栓栓塞症的治療和預防可能需要更加完善，特別是針對發生靜脈血栓栓塞症危險性較高的病人。

關鍵詞靜脈血栓栓塞症、癌症、流行病學、治療現狀、危險因子、全民健康保險研究資料庫

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Abstract

Background Venous thromboembolism (VTE) is an increasing clinical problem in

cancer patients that results in significant mortality and morbidity. Reports indicated that

the incidence of VTE varies among different ethnic populations. Although the clinical

guidelines for the prevention of VTE have been suggested in Western countries, the

understanding of the epidemiology of VTE in Asian countries remains limited.

Objectives The goal of this population-based observational study is to explore the

epidemiology of VTE among cancer patients in Taiwan, analyze the risk factors for

VTE and describe the clinical characteristics and treatment pattern of VTE

Methods Using three sets of longitudinal health insurance database (LHID 2000, LHID

2005 and LHID 2010), we identified newly diagnosed cancer patients who have been

hospitalized with a primary diagnosis of malignant disease between 2001 and 2008. The

date when the patient was first hospitalized with a primary diagnosis of malignant

disease was defined as the index date. Patients had more than one primary diagnosis of

malignant diseases at index date were excluded. Primary endpoint of our study was

hospital admission for VTE during or after index date. Two definitions of VTE were

adopted in our study. VTE definition 1 was based on VTE diagnosis codes in the

inpatient medical claims. VTE definition 2 was based on both the VTE diagnosis codes

and management of VTE. The incidence rates of VTE for the entire study cohort and

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subgroups of patients categorized by sites of cancer were estimated. Differences in age,

gender, comorbidities, and potential risk factors for VTE between patients with and

without VTE events were analyzed. We use t-test for continuous variables and

Chi-square analysis or Fisher’s exact test for discrete variables. Only patients who

hospitalized with VTE (definition 2) were included in the logistic regression model to

identify the risk factors for VTE. We also describe the long-term treatment pattern of

VTE and incidence rates of recurrent VTE and bleeding complications.

Results Among 43,855 newly diagnosed cancer patients, 1388 (3.2%) (definition 1) and

473 (1.1%) (definition 2) patients were hospitalized for VTE during or after index date.

The incidence rates of VTE (definition 1 and definition 2) were 9.9 per 1,000

person-years (1.0-68.2 per 1,000 person-years) and 3.4 per 1,000 person-years (0.0-16.1

per 1,000 person-years), respectively. The incidence rates were higher in certain cancers,

particularly cancer of liver, pancreas, lung, multiple myeloma, sarcoma, and

non-Hodgkin’s lymphoma. The cumulative occurrence of VTE (definition 1) within 30,

90, 180, and 365 days after index date were 42.9%, 53.5%, 61.7%, and 70.8%,

respectively. Cumulative occurrence of VTE (definition 2) within 30, 90, 180, and 365

days after index date were 25.2%, 39.8%, 47.8% and 59.4%, respectively. Significant

risk factors for VTE were site of cancer, prior history of VTE, arterial embolism, obesity,

hypertension, rheumatologic diseases, chemotherapy, combination therapy and major

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thoracic, abdominal or urogenital surgery. In contrast, blood transfusion within 3

months was significant associated with reduced risk of VTE. Among 1388 patients who

hospitalized with VTE (definition 1), only 33.6% of patients (n=467) received

anticoagulant therapy or thromboectomy during the hospitalization. Among 473 patients

who hospitalized with VTE (definition 2), 1.5% of patients received thromboectomy,

other patients received heparin or low molecular weight heparin for initial treatment of

VTE. Eighty-one patients (19.5%) had recurrent VTE after the first VTE event. Of 415

survived patients, long-term anticoagulant therapy was initiated in 266 patients (64.1%),

72.2% of them (n=192) received warfarin alone. The median duration was 66 days.

Approximately two-thirds of patients (58.7%, n=156) received ≤ 3 months of long-term

anticoagulant therapy.

Conclusions Although the incidence of cancer-related VTE among Taiwanese is lower

than Caucasians populations, it is much higher than Asian general populations,

particularly in patients with certain cancers such as multiple myeloma, pancreas, liver,

and lung cancer. Most VTE occurred within 1 year after cancer diagnosis. Adherence to

treatment guidelines was poor in Taiwan. Treatment and prophylaxis of VTE should be

optimized, especially in patients with higher-risk of VTE.

Keywords Venous thromboembolism, cancer, epidemiology, clinical profile, risk factors,

National Health Insurance Research Database

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List of Figures

Figure 4.1 Initial and long-term treatment for VTE ... 42

Figure 4.2 Study framework - risk factors for VTE development among cancer patients

... 46

Figure 5.1 Flowchart of the population-based study ... 48

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List of Tables

Table 2.1 Incidence of venous thromboembolism reported in different populations ... 4

Table 2.2 Risk factors for venous thromboembolism ... 6

Table 2.3 Cohort studies of incidence of venous thromboembolism in patients hospitalized with cancer ... 12

Table 2.4 Cohort studies of incidence of venous thromboembolism in ambulatory cancer patients receiving active therapy ... 13

Table 2.5 Risk factors for venous thromboembolism in patients with malignant disease ... 16

Table 2.6 Regimens for prophylaxis/treatment of VTE in patients with cancer ... 22

Table 2.7 Recommendations for treatment of VTE in cancer patients ... 23

Table 2.8 Recommendations for prophylaxis of VTE in cancer patients ... 28

Table 2.9 Cohort studies of incidence of venous thromboembolism in patients of specified cancer site among Asian population ... 31

Table 4.1 ICD-9-CM codes of inclusion diagnosis ... 35

Table 4.2 ICD-9-CM diagnosis codes of venous thromboembolism ... 37

Table 4.3 Anatomic distribution of VTE and relevant ICD-9-CM codes ... 38

Table 4.4 List of hormone therapy ... 41

Table 4.5 Bleeding complications and relevant ICD-9-CM codes ... 43

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Table 5.1 Site of cancer and associated incidence rate of VTE (VTE definition 1) ... 51

Table 5.2 Site of cancer and associated incidence rate of VTE (VTE definition 2) ... 53

Table 5.3: Time-to-VTE after cancer diagnosis ... 56

Table 5.4 Anatomic distribution of VTE ... 56

Table 5.5: Baseline characteristics of the study population (VTE definition 1) ... 59

Table 5.6 Potential risk factors for development of VTE (VTE definition 1) ... 60

Table 5.7: Baseline characteristics of the study population (VTE definition 2) ... 63

Table 5.8: Potential risk factors for development of VTE (VTE definition 2) ... 64

Table 5.9 Multivariate analysis of risk factors for VTE... 66

Table 5.10 Initial treatment of VTE during the hospital admission for VTE ... 69

Table 5.11 Anticoagulants administered during long-term treatment ... 70

Table 5.12 Duration of long-term anticoagulant therapy ... 70

Table 5.13 Cumulative rates of VTE recurrence ... 71

Table 5.14 Recurrence of VTE and bleeding complications during long-term anticoagulant treatment ... 72

Table 6.1 Sensitivity analysis of risk factors for VTE ... 83

Table 6.2 Clinical studies of long-term treatment of VTE among cancer patients ... 87

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Chapter 1 Introduction

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and

pulmonary embolism (PE), is an increasing clinical problem in cancer patients that

results in significant mortality and morbidity. Cancer patients have 4- to 7- folds higher

risk for VTE than general population, occurring in 4% to 20% of patients.^1,2 Use of

anticoagulants, increased risk of VTE recurrence, bleeding complications during

anticoagulant therapy, post-thrombotic syndrome and reduced lung function due to

chronic thrombotic pulmonary hypertension further complicate the clinical management

of cancer and worsen patients’ quality of life.^3,4 Besides, cancer patients who develop

VTE have a significant worse survival and this effect is more pronounced in patients

with loco-regional disease rather than distant metastatic disease.^5-7

Solid tumors of gastrointestinal (GI) tract, lungs, pancreas, ovaries, and

hematological malignancies are associated with high risk of VTE, with the highest risk

occurring during the initial period after cancer diagnosis.^5,9-11 Other risk factors for VTE

among cancer patients including older age, metastatic stage, prior history of VTE,

presence of indwelling central venous catheter (CVC), chemotherapy or hormone

therapy, major surgery, inherited or acquired thrombophilia, and elevated

pre-chemotherapy platelet count.¹

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The incidence of VTE in Asian population has been perceived to be lower than

Caucasian population. However, the incidence of VTE in Asian population increased

rapidly by 56% from 2004 to 2008.⁸ Increased awareness of physicians, easier diagnosis

of VTE, growing elderly population, and a Westernized lifestyle may contribute to this

increasing trend.⁹ While several nationwide epidemiologic studies had been performed

using Taiwan’s and Korea’s National Health Insurance (NHI) database to understand the

incidence and risk factors for VTE among the general population, only few in cancer

patients. ^8,10,11

In addition, existing studies among Asian populations only focused on patients with

colorectal, gastric, and pancreatic cancers, diffuse large B cell lymphoma, and multiple

myeloma.^12-18 Furthermore, very few Small numbers of patients were included in these

studies. Most existing studies only included patients from one medical center.^12-18 Up to

know, the clinical significance of VTE among cancer patients, and the epidemiological

study of VTE across various cancer subtypes have never been conducted in Asian

populations. Given the growing incidence of cancer and elderly population, burden of

VTE is expected to be increased. An epidemiological study will help us to understand

the incidence and treatment of VTE among cancer patients and optimize the clinical

practice. Therefore, a population-based study was performed using the Taiwan’s NHI

database to understand the epidemiology and clinical profile of VTE in cancer patients.

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Chapter 2 Literature Review

2.1 Venous Thromboembolism

2.1.1 Overview of Venous Thromboembolism

VTE refers to all forms of pathologic thrombosis occurring within the venous

circulation, represents a spectrum from simple superﬁcial thrombophlebitis to fatal

pulmonary embolism. Most venous thrombosis occurs at the deep veins of the lower

extremities, giving rise to deep vein thrombosis (DVT). They also can occur in other

parts of body, including the veins of the upper extremities, pelvis, abdomen, and

cerebral venous sinuses. Pulmonary embolism (PE) is the most life-threatening

manifestation of VTE, which occurs when a clot dislodges from the site of formation

and embolizes into pulmonary arteries. Death from PE can occur within minutes after

the onset of symptoms, before effective treatment is given.^19,20

2.1.2 Epidemiology of Venous Thromboembolism

The actual incidence of VTE is unknown because the disease is often clinically

silent. The annual incidence rate of VTE is reported to be 104-183 events per 100,000

persons in the Caucasian populations (Table 2.1).^21-25 The annual incidence of VTE

increases markedly with age, from less than 5 cases per 100,000 persons under 15

year-old to 149 events per 100,000 persons over the age of 80.²¹

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The prevalence of VTE varies among different ethnic cohorts. Compared to

Caucasian populations, the incidence of VTE is significantly higher among African-

American and significantly lower among Asian populations.^22,26,27 Among Asian

populations, the estimated annual incidence of VTE is 14-57 per 100,000 persons (Table

2.1).^8,10,28,29 The incidence ranges from 2.5 events per 100,000 person-years in those

younger than 30 years to 100 events per 100,000 person-years in those aged over 80

years.¹⁰ Although the annual incidence of VTE among Asian populations has been

perceived to be lower than Caucasian populations, it appears to be rapidly increasing.^8,30

Along with rapid aging of the population, VTE is a major healthcare problem which

causing significant mortality, morbidity and healthcare resource expenditure in our

aging society.

Table 2.1 Incidence of venous thromboembolism reported in different populations Incidence per 100,000

Location Study design VTE DVT PE

America

Minnesota (Silverstein et al. 1998)²¹ California (only Caucasian)²² (White et al. 2005)

Worcester (Spencer et al. 2009)³¹

Population-based study Population-based study

Population-based study

117 104

114

48

95

69

34 Europe

French (Oger et al. 2000)²⁴ Norway (Naess et al. 2007)²⁵

Population-based study Cohort-study

183 143

124 93

60 50 Asia

Hong Kong (Cheuk et al. 2004)²⁸ Singapore (Molina et al. 2009)²⁹ Taiwan (Lee et al. 2010)¹⁰ Korea (Jang et al. 2011)⁸

Population-based study Population-based study Population-based study Population-based study

21 57 15.9 13.8

17

5.31

3.9

7.01

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2.1.3 Risk Factors for Venous Thromboembolism

VTE is a multifactorial condition involving genetic and both constant and transient

acquired risk factors. In 1884, Virchow’s triad first described three primary factors

contribute to the formation of thrombosis: abnormalities in blood flow (venous stasis),

abnormalities in blood constituents (hypercoagulability), and abnormalities in the vessel

wall (vascular endothelial injury). Risk factors for VTE, include increasing age,

malignancy, prolonged immobility, major surgery, major trauma, prior VTE, chronic

heart failure, and inherited or acquired thrombophilia, alter one or more of the

components of the triad (Table 2.2).³² There is convincing evidence that the risk of VTE

increases in proportion to the number of predisposing factors.^32,33

Compared with residents in the community, hospitalization without surgery or

nursing home confinement is associated with 8-folds increased risk of VTE.³⁴

Hospitalization and nursing home residence together account for almost 60% of incident

VTE events occurring in the community, with hospitalization for medical illness and

hospitalization for surgery accounted for 22% and 24% of VTE, respectively.²

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Table 2.2 Risk factors for venous thromboembolism Strong risk factors (odd ratio > 10)

Fracture (hip or leg) Hip or knee replacement Major general surgery Major trauma

Spinal cord injury

Moderate risk factors (odd ratio 2-9) Arthroscopic knee surgery

Central venous lines Chemotherapy

Congestive heart or respiratory failure Hormone replacement therapy

Malignancy

Oral contraceptive therapy Paralytic stroke

Pregnancy (postpartum)

Previous venous thromboembolism Thrombophilia

Weak risk factors (odd ratio < 2) Bed rest > 3 days

Immobility due to sitting (e.g. prolonged car or air travel) Increasing age

Laparoscopic surgery (e.g. cholecystectomy) Obesity

Pregnancy (antepartum) Varicose veins

Adapted from Anderson FA, Jr., Spencer FA. Risk factors for venous thromboembolism.

Circulation 2003;107:I9-16.

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2.1.4 Complications of Venous Thromboembolism

VTE is an important worldwide healthcare burden associated with significant

morbidity and mortality. It is reported to be the third common cardiovascular causes of

death after myocardial infarction and stroke.³⁵ The 1-week survival rate after a PE is

only 71%, and almost 25% of all cases of PE essentially present as sudden death.³⁶ In

USA, 100,000-300,000 VTE-related deaths occur every year and PE had been declared

to be the most common preventable cause of hospital death and the significant target to

improve patient safety in hospitals.³⁷

Recurrence of VTE is common. Despite anticoagulant therapy, about 30% of

patients develop recurrent VTE within the next ten years, with the highest recurrence

rate within the first year after their first VTE event.^38,39 Men have a higher rate of

recurrence than women (relative risk of recurrent VTE: 1.6).^40,41 In addition, survivors

of VTE always suffer from long-term complications, including post-thrombotic

syndrome and chronic thrombotic pulmonary hypertension. One-third to one-half of

patients with lower extremity DVT develop post-thrombotic syndrome during 20 years

of follow-up, characterized by pain and swelling, and in severe cases with venous

ulceration. These conditions can be disabling for patients and have great impact on

healthcare costs. Subsets of VTE patients require long-term anticoagulation to prevent

additional clots, which also decreases their quality of life and places them at an

(23)

8

increased risk for adverse bleeding episodes.^37,38

2.1.5 Clinical Presentations of Venous Thromboembolism

The signs and symptoms of VTE are nonspecific. Furthermore, many patients with

VTE were asymptomatic. A leg DVT commonly presents with pain, erythema, and

swelling of the affected limb. Physical examination may show palpable cord, warmth,

and unilateral edema.^42,43 Patients with upper extremity or neck DVT often complain

with upper extremity or head or neck swelling, erythema, and/or discomfort.⁴⁴

Symptoms associated with PE depend on the degree of vascular obstruction, the

magnitude of inflammatory response, and the patient’s cardio-pulmonary reserve.

Patients may present with dyspnea, hypoxemia, tachycardia, pleuritic chest pain,

hemoptysis or even collapse with shock or pulseless electrical activity cardiac arrest.^20,43

2.1.6 Diagnosis of Venous Thromboembolism

Duplex ultrasonography remains the test of choice in the investigation and

diagnosis of clinically suspected DVT. Although ultrasound is highly sensitive for the

detection of proximal DVT, it is less accurate for isolated DVT of the calf. The ideal

method, invasive venography, is used when a definitive answer is required. Newer

image modalities such as magnetic resonance venography and computerized

(24)

9

tomography (CT) scan can detect thrombosis of vessels proximal to the inguinal

ligament and intra-abdominal vessels. Another advantage of magnetic resonance

venography and CT scan is their ability to provide information about surrounding

structures that may lead to alternative diagnosis.^20,42-44

Gold standard for the diagnosis of PE is pulmonary angiography, but it is an

invasive procedure that involves injection of contrast dye into pulmonary artery and

associated with 0.5% of mortality. Nowadays, CT scan has become the most commonly

used imaging test to diagnose PE. Before CT scan, ventilation-perfusion (V/Q) scan was

the first-line imaging modality of PE. Spiral CT scan can detect emboli in the

pulmonary arteries whereas V/Q scan measures the distribution of blood and air flow in

the lungs.^20,42,43

(25)

10

2.2 Venous Thromboembolism in Patients with Cancer

2.2.1 Overview

VTE is a major complication of cancer and is one of the leading causes of death in

patients with cancer.^1,4,45 The risk of VTE is higher in cancer patients than the general

population, especially hospitalized patients with cancer and those receiving active

therapy. In a population-based study, malignancy alone was associated with a 4-folds

increased risk of VTE, whereas the use of chemotherapy increased the risk to

6.5-folds.³⁴ Overall, approximately 20% to 39% of VTE cases were attributable to

active malignant disease.^33,46

2.2.2 Epidemiology of Cancer-related VTE

The reported incidences of VTE in cancer patients have varied widely, with

reported incidences ranging from 0.6% to 12.1% (Table 2.3 and 2.4).^47-54 However, the

reported rates of VTE in cancer patients are believed to be underestimated, given that

autopsy rates of VTE can be as high as 50% compared with clinical rates of 4% to

20%.¹ In addition, the burden of VTE in cancer patients is increasing. In previous study,

the rate of VTE event in cancer patients increased by 28% over the period 1995–2003 (p

< 0.0001 for the trend).⁵¹

The risk of postoperative VTE in cancer patients also exceeds that of non-cancer

(26)

11

surgical patients by 2- to 3-folds. Without anticoagulant prophylaxis, the incidence of

postoperative DVT ranges from 40% to 80%.⁵⁵ In an observation study using

administrative database, the rate of VTE in cancer patients within 30 days

post-admission after major surgery was 3.5%, with ranging by procedure from 1.8 to

13.2%.⁵⁶ Another prospective study, focused on postoperative clinical overt VTE,

reported an incidence of 2.1% even when in-hospital prophylaxis was given in 81.6% of

the patients. The 30-day mortality was 1.7% and VTE was adjudicated as the most

common of death (19 of 41 cases, 46.3%) in the study.⁵⁷

2.2.3 The Pathogenesis of VTE in Cancer

Cancer cell may induce thrombosis by triggering several complex prothrombotic

pathways, including procoagulant effects of tissue factors expressed by tumor cells, the

release of cytokines, the inhibition of ﬁbrinolysis, and the overexpression of membrane

adhesion molecules. Furthermore, solid tumor-mediated extrinsic vascular compression

and invasion can obstruct venous return, resulting in blood flow stasis, endothelial cell

injury, and coagulation activation. Malignancy-associated inflammation can also result

in increased concentrations of acute-phase proteins such as factor VIII, fibrinogen, and

von Willebrand factor. Elevations of these acute-phase proteins are associated with an

increased risk of thrombosis.^3,58

(27)

12

Table 2.3 Cohort studies of incidence of venous thromboembolism in patients hospitalized with cancer

Location Data source Study population Study endpoint No. of

patients

VTE event (%)

USA

Levitan et al. (1999)⁴⁷

Medicare database Patients ≥ 65 years with malignant disease

Hospital admission for DVT and/or PE

1,211,944 0.6

(0.16-1.20) USA

Sallah et al. (2002)⁴⁸

Medical records of University of Tennessee Health Science Center, University of North Carolina at Chapel Hill, and East Carolina University

Patients with solid tumor Objectively confirmed DVT and/or PE

1,041 7.8

USA

Stein et al. (2006)⁴⁹

National Hospital Discharge Survey

Patients with malignant disease

Hospital admission for DVT and/or PE

40,787,000 2.0

(0.60-4.30) USA

Khorana et al. (2006)⁵⁰

Discharge database of the University Healthsystem Consortium

Adult cancer patients with febrile neutropenia

Hospital admission for VTE

5,272 5.4

(2.74-12.10)

USA

Khorana et al. (2007)⁵¹

Discharge database of the University Healthsystem Consortium

Adult patients with solid tumor

1,015,598 4.1

(1.90-8.10)

Denmark

Cronin-Fenton et al.

(2010)⁵²

Database of Danish National Registry of Patients, Danish Cancer Registry and Danish Civil Registration System

Patients ≥ 15 years with malignant disease

57,591 1.8

(0.80-4.00)

(28)

13

Table 2.4 Cohort studies of incidence of venous thromboembolism in ambulatory cancer patients receiving active therapy

patients

VTE event (%)

USA

Khorana et al. (2005)⁵³

Database of Awareness of Neutropenia in Cancer Study Group Registry

Patients ≥ 18 years with histologically confirmed diagnosis of cancer

VTE 3,003 1.93

USA

Shah et al. (2010)⁵⁴

Clinical trial research database of Merorial Sloan Kettering Cancer Center

Patients ≥ 18 years with non-hematologic

malignancies

Objectively confirmed DVT/PE

2,120 5.45

(29)

14

2.2.4 Risk Factors for Cancer-related VTE

Despite the overall increased risk of VTE among cancer patients, VTE risk is

especially high among certain subgroups, such as hospitalized patients, those receiving

active neoplastic therapy or hormone therapy, those undergoing major surgery, and

those with metastatic disease. The risk of VTE differs across various cancer subgroups

and over the natural history of cancer. Sites of cancer with highest rates of VTE include

pancreas, stomach, brain, ovary, kidneys, lungs, and hematologic malignancies, such as

multiple myeloma and non-Hodgkin’s lymphoma. The risk of VTE is highest in the

initial period after the cancer diagnosis.^1,4,5,51

Cancer patients receiving active therapy are at greater risk of VTE. In a

retrospective cohort study of 1,015,598 cancer patients, use of chemotherapy is

identified to be an independent risk factor for VTE.⁵¹ Recent study among

chemotherapy-treated patients with lung cancer found that use of chemotherapy is

associated with 30% greater risk of VTE compared with patients not receiving

chemotherapy.⁵⁹ Hormone therapy (such as tamoxifen) and antiangiogenic drug (such as

bevacizumab) have been associated with an increased risk of VTE.^1,60,61 Among patients

with multiple myeloma, the risk of VTE is higher in whom receiving thalidomide or

lenalidomide in combination with dexamethasone or chemotherapy. Besides,

erythropoietin-stimulating agents (ESA) are also associated with an increased risk of

(30)

15

VTE.¹

Other risk factors for VTE among cancer patients include increasing age, prior

history of VTE, pre-chemotherapy platelet count ≥ 350,000 μL, the presence of

prothrombotic mutation, placement of CVC, and concomitant comorbid conditions.

Race is also a significant factor associated with VTE risk. Compared with Caucasian

patients with cancer, Asian patients with cancer have significant reduced risk of

VTE.^6,7,51 A comprehensive list of risk factors associated with VTE in cancer patients is

summarized in Table 2.5.¹

(31)

16

Table 2.5 Risk factors for venous thromboembolism in patients with malignant disease Patient-related factors

Older age

Race (higher in African Americans; lower in Asian-Paciﬁc Islanders)

Comorbid conditions (obesity, infection, renal disease, pulmonary disease, arterial thromboembolism)

Prior history of VTE

Elevated pre-chemotherapy platelet count Heritable prothrombotic mutations

Cancer-related factors

Primary site of cancer (GI, brain, lung, gynecologic, renal, hematologic) Initial 3-6 months after diagnosis

Current metastatic disease Treatment-related factors

Recent major surgery Current hospitalization Active chemotherapy Active hormonal therapy

Current or recent antiangiogenic therapy (thalidomide, lenalidomide, bevacizumab^*)

Current erythropoiesis-stimulating agents Presence of central venous catheters

* Bevacizumab is clearly associated with an increased risk of arterial thrombotic events; an association with venous thrombosis is not fully established.

Adapted from Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25:5490-505.

(32)

17

2.2.5 Consequences of Cancer-related VTE

VTE is associated with significant morbidity and mortality among cancer patients.

In a retrospective analysis based on California cancer registry, development of VTE

after cancer diagnosis was a significant predictor of mortality within 1 year, with hazard

ratios (HR) ranging from 1.6 to 4.2 (p < 0.01). The strongest predictor of death in that

study was metastatic disease at the time of cancer diagnosis, with an HR ranging from

1.8 to 49.0 (p<0.001).⁷ Similar finding was shown in another retrospective study

included hospitalized neutropenic cancer patients. Patients with VTE had 2-folds greater

risk of mortality than patients without diagnosis of VTE.⁵⁰ Studies in patients with

colorectal, lung and breast cancer in California also found that VTE is a significant

predictor of death within 1 year of cancer diagnosis. The effect was more pronounced in

patients with loco-regional stage rather than patients with advanced and metastatic

disease.^6,7,62 Similar finding was found in other studies in patients with pancreatic,

gastroesophageal, bladder, and ovarian cancer.^54,63-65

VTE is also associated with hospitalization, anticoagulants use, reduced pulmonary

function, and post-thrombotic syndrome. The occurrence of VTE may interfere with

planned chemotherapy and causes treatment delay.⁴ Furthermore, compared with

general population, the risk of recurrent VTE and bleeding complications during

anticoagulant treatment in cancer patients was increased about 4 times and 2 times,

(33)

18

respectively.⁶⁶ The occurrence of VTE worsens patients’ quality of life and lead to

increased consumption of healthcare resource. In a retrospective study of medical

records of 529 cancer patients using medical records as the data source, the mean

hospitalization cost for DVT was $20,065 per episode (2002 US$) compared with a cost

of $7712 to $10,804 per episode in a general medical population with VTE.⁶⁷

2.2.6 Treatment of Venous Thromboembolism in Cancer Patients

In response to the increasing concern regarding VTE in cancer patients, several

international cancer organizations have recently issued guidelines regarding its

treatment and prevention. These include the Italian Association of Medical Oncology

(AIOM),⁶⁸ the National Comprehensive Cancer Network (NCCN),⁶⁹ the American

Society of Clinical Oncology (ASCO),¹ the European Society of Medical Oncology

(ESMO),⁷⁰ and the French National Federation of the League of Centers Against Cancer

(FNCLCC).^71,72 Anticoagulant therapy remains the cornerstone of VTE treatment.

Anticoagulant therapy is divided into two phases: initial treatment to minimize the risk

of thrombus extension and subsequent fatal PE, and long-term treatment to prevent

recurrent VTE, thereby reducing the risk of post-phlebitic syndrome.⁷³

(34)

19

2.2.6.1 Initial Treatment of Venous Thromboembolism

When VTE is objectively confirmed, parenteral anticoagulants should be initiated.

Treatment is started with unfractionated heparin (UFH), low molecular weight heparin

(LMWH) or fondaparinux. Agent selection should be individualized according to

characteristics of the individual agents (ease of administration, reversibility, half-life,

and cost) and patient’s clinical situation (inpatient or outpatient status, renal function,

medical or surgical patient). In most circumstances, LMWH is preferred because it is

recommended for the long-term treatment of VTE in patients with cancer and facilitates

the transition to outpatient management. 1,44,69-71

Furthermore, LMWH and fondaparinux

provide additional advantages over UFH, including better bioavailability after

subcutaneous administration, longer half-life, more predictable anticoagulant response

and lower incidence of heparin-induced thrombocytopenia.⁷⁴ LMWH should be used

cautiously in patients with creatinine clearance (CCr) < 30 mL/min and fondaparinux is

contraindicated in these patients.^1,69,70

2.2.6.2 Long-term Treatment of Venous Thromboembolism

After initial treatment for 5 to 10 days, LMWH is the preferable approach for

long-term treatment lasting at least 3 to 6 months for patients with VTE. Vitamin K

antagonists (VKA) with a target international normalized ratio (INR) of 2 to 3 are

(35)

20

considerable choice for long-term treatment when LMWH is not available or in patients

with severe renal insufficiency. Indefinite therapy may be required for patients with

active cancer, such as those with metastatic disease and those receiving chemotherapy

or hormonal therapy. ^1,69,70,75 Although enoxaparin and tinzaparin also have been studied

in open-label randomized controlled trials in cancer patients, the efficacy of dalteparin

is supported by the highest quality evidence and it is the only LMWH approved by the

FDA for long-term treatment of VTE in cancer patients.⁶⁹ Randomized controlled trials

indicate that LMWH is more effective than VKA in long-term treatment for preventing

VTE recurrence with similar bleeding risk.^76-79 The CLOT (Randomized Comparison of

LMWH versus Oral Anticoagulant for The Prevention of Recurrent VTE in Patients

with Cancer) study demonstrated a relative risk reduction of 49% with LMWH versus a

VKA.⁷⁷ In patients with contraindications to anticoagulation, inferior vena cava filter is

an alternative but anticoagulant therapy should be resumed once the bleeding risk is

resolved. Dosage regimens and recommendations for treatment of VTE in patients with

cancer are provided in Table 2.6 and 2.7.^1,69,70,75

On the other hand, cancer patients are more likely to have thrombosis in

uncommon sites such as the veins of upper extremities, vena cava, visceral, portal, or

cerebral circulation.⁸⁰ There are no specific guidelines and randomized controlled trials

focus on the treatment of abdominal DVT in cancer patients or non-cancer patients.

(36)

21

Recently, the 9^th American College of Chest Physicians (ACCP) guidelines published in

2012 recommend anticoagulation over no anticoagulation in patients with symptomatic

splanchnic vein thrombosis.⁷⁵

Treatment of VTE in cancer patients is more challenging than general population.

Compared with those without malignancy, VTE recurs 3-folds more frequently in

cancer patients and they are more prone to bleeding complications during long-term

treatment of VKA therapy despite a stable INR between 2 to 3. Interactions between

VKA and chemotherapeutic agents may cause elevation of INR and clinically relevant

bleeding. Tendencies toward thrombocytopenia, osteopenia, malnutrition, brain

metastasis and hepatic metastasis all further complicate thrombosis care in cancer

patients.^3,55

(37)

22

Table 2.6 Regimens for prophylaxis/treatment of VTE in patients with cancer

Management Drug Regimen

Prophylaxis

Hospitalized medical or surgical cancer patients

Unfractioned heparin Dalteparin

Enoxaparin Fondaparinux

5,000 U every 8 hours 5,000 U daily

40 mg daily 2.5 mg daily Treatment of established VTE

Initial

Long term

Heparin

Dalteparin

Enoxaparin

Tinzaparin Fondaparinux

Dalteparin

Warfarin

80 U/kg IV bolus, then 18 U/kg/h IV

100 U/kg every 12 hours 200 U/kg daily

1 mg/kg every 12 hours 1.5 mg/kg daily

175 U/kg daily

< 50 kg, 5.0 mg daily 50-100 kg, 7.5 mg daily

> 100 kg, 10.0 mg daily 200 U/kg daily for 1 month;

then 150 U/kg daily 5-10 mg PO daily; adjust dose to INR 2-3

Adapted from Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25:5490-505.

(38)

23

Table 2.7 Recommendations for treatment of VTE in cancer patients

ASCO¹ NCCN⁶⁹ ESMO⁷⁰ ACCP⁷⁵

Initial treatment of VTE

LMWH is the preferred approach for the initial 5-10 days

LMWH, UFH or fondaparinux according to patient’s

characteristics and clinical situation

Weight-adjusted dose LMWH.

If Ccr < 25-30 mL/min, either UFH or LMWH with anti-Xa monitoring

Suggest LMWH or

fondaparinux over UFH for minimum of 5 days

Long-term treatment of VTE

LMWH for at least 6 months is preferred; VKA are

acceptable when LMWH is not available. Indeﬁnite anticoagulation in patients with active cancer

LMWH is preferred; 3-6 months for DVT and 6-12 months for PE. Indeﬁnite anticoagulation in patients with active cancer or persistent risk factors

LMWH is preferred for 6 months with 75-80% of the initial dose. Long-term LMWH for patients with active cancer

Suggest extended

anticoagulant therapy (~3 months to indefinite);

LMWH is preferred over VKA therapy

Thrombolytic therapy in the initial

treatment

Restricted to patients with life- or limb-threatening thrombotic events

Patients with massive PE or submassive PE with moderate or severe RV enlargement or dysfunction

Restricted to patients with PE presenting with severe RV dysfunction, or limb-

threatening thrombotic events

Restricted to patients with massive PE and impending venous gangrene

Inferior vena cava filters

Restricted to patients with contraindications to

anticoagulation or recurrent VTE despite adequate long- term LMWH

Contraindications to failure of anticoagulation; cardiac or pulmonary dysfunction severe enough to make any new PE life-threatening or multiple PE with chronic pulmonary hypertension

Contraindications to

anticoagulation or recurrent PE despite adequate long- term LMWH. Resume

anticoagulation on the risk of bleeding is reduced

Contraindications to

anticoagulation or recurrent PE despite adequate long- term LMWH. Start

anticoagulation if the risk of bleeding is resolved

(39)

24

Table 2.7 Recommendations for treatment of VTE in cancer patients (continued)

ASCO¹ NCCN⁶⁹ ESMO⁷⁰ ACCP⁷⁵

Treatment of catheter- related thrombosis

NA Anticoagulation for as long

as catheter is in place and for at least 3 months after catheter removal

NA 3 months of anticoagulation

if the catheter is removed;

continue anticoagulation as long as the CVC remains Abbreviations: VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; ASCO, American Society of Clinical Oncology; NCCN, National Comprehensive Cancer Network; ESMO, European Society of Medical Oncology; UFH, unfractionated heparin;

LMWH, low molecular weight heparin; VKA, vitamin K antagonist; RV, right ventricular; Ccr, creatinine clearance; NA, not addressed.

(40)

25

2.2.7 Prevention of Venous Thromboembolism in Cancer Patients

2.2.7.1 Prevention of VTE in Cancer Patients Undergoing Surgery

Cancer patients who undergo surgery are at high risk of developing VTE. Post-

operative VTE occurs 2- to 3-folds more frequent in cancer patients compared with

non-cancer patients. Prophylaxis of VTE with low-dose UFH, LMWH or fondaparinux

is recommended in all patients undergoing major surgery (such as laparotomy,

laparoscopy, or thoracotomy lasting > 30 minutes). Pharmacological prophylaxis should

be started as soon as possible and continued for at least 7 to 10 days postoperatively

unless contraindicated. Extended prophylaxis up to 4 weeks may be considered in

patients undergoing major abdominal or pelvic surgery for cancer patients with

high-risk features such as residual malignant disease after operation, obese patients, and

those with a previous history of VTE. ^1,69,70

LMWH has shown to be as effective and safe as low dose UFH in preventing

post-operative VTE.^81-83 In a double-blind randomized trial of fondaparinux versus

dalteparin in high-risk abdominal surgery patients, postoperative fondaparinux was at

least as effective as perioperative dalteparin.⁸⁴ However, after pooling the results of

studies in patients undergoing elective hip replacement, elective knee replacement, and

hip fracture surgery, it is suggested that compared to LMWH, fondaparinux does not

reduce clinically significant VTE events but leads to more major bleeding events.⁷⁵

(41)

26

Mechanical prophylaxis such as pneumatic calf compression (IPC) may be added

to pharmacological prophylaxis but should not be used as monotherapy for VTE

prevention unless pharmacological prophylaxis is contraindicated because of active

bleeding.^1,70 Mechanical prophylaxis alone can reduce the rate of DVT by 66% but

achieve only a non-statistical 33% risk reduction in the rate of PE.⁵⁵ Combination of

mechanical and pharmacological prophylaxis may improve efficacy in the very high

risk patients.¹ Dosage regimens and recommendations for prevention of VTE in patients

with cancer are provided in Table 2.6 and 2.8.^1,69,70

2.2.7.2 Prevention of Hospitalized and Ambulatory Cancer Patients

Hospitalized cancer patients should be considered to receive anticoagulation for

prevention of VTE.^1,69,70 Among patients hospitalized for cancer, chronic heart disease,

severe infectious diseases, or lung disease, cancer patients had the highest incidence of

VTE (7.6%) compared to the average rate of all patients being 5.6%.⁸⁵ Previous

randomized clinical trials have demonstrated that pharmacological prophylaxis leads to

a lower VTE incidence compared with placebo, without increasing major bleeding.^86-88

Routine prophylaxis with anticoagulants is not recommended in ambulatory

patients with cancer except patients with multiple myeloma receiving thalidomide or

lenalidomide with chemotherapy or dexamethasone. ESMO guideline recommended

(42)

27

LMWH, aspirin, or adjusted-dose warfarin (INR ~1.5) while ASCO guideline

recommended LWMH or adjusted-dose warfarin (INR ~1.5). Prophylaxis in cancer

patients receiving chemotherapy and/or hormone therapy is not recommended.^1,70 For

cancer patients with indwelling CVC, benefit of pharmacological prophylaxis had not

been shown. Current guidelines do not support the use of anticoagulants for VTE

prophylaxis.^70,72

(43)

28

Table 2.8 Recommendations for prophylaxis of VTE in cancer patients

ASCO¹ NCCN⁶⁹ ESMO⁷⁰

Hospitalized cancer patient

 Prophylactic anticoagulation should be considered in the absence of bleeding or other contraindications to anticoagulation

Surgical cancer patient

 All patients undergoing major surgical* intervention for malignant disease should be considered for thromboprophylaxis, commenced preoperatively, or as early as possible postoperatively and continue for 7 to 10 days.

 Extended prophylaxis up to 4 weeks in patients undergoing major

abdominal or pelvic surgery for cancer with high-risk features such as residual disease, obesity, or prior VTE

 Pharmacologic thromboprophylaxis should be used in the absence of contraindications

 Prophylaxis should be continue for the duration of hospitalization

 Extended prophylaxis up to 4 weeks after surgery for high-risk abdominal or pelvic surgery, defined by

gastrointestinal malignancy, prior VTE, anesthesia time > 2 hours, bed rest > 4 days, advanced stage, age >

60 years

 Thromboprophylaxis should be considered in all patients undergoing major cancer surgery*

 Prophylaxis should be continued for at least 10 days postoperatively

 Extended prophylaxis up to 1 month after surgery in cancer patients undergoing elective major abdominal or pelvic surgery

Ambulatory patient

 Not recommended with the exception of LMWH, aspirin or adjusted- dose warfarin (INR ~1.5) in patients with multiple myeloma receiving thalidomide- or lenalidomide-based combination regimens

Patients with CVC

 NA  Prophylactic anticoagulation is not

recommended

 Prophylactic anticoagulation is not recommended

* Laparotomy, laparoscopy, or thoracotomy lasting > 30 minutes

Abbreviations: VTE, venous thromboembolism; ASCO, American Society of Clinical Oncology; NCCN, National Comprehensive Cancer Network; ESMO, European Society of Medical Oncology; LMWH, low molecular weight heparin; NA, not addressed.

(44)

29

2.2.8 Venous Thromboembolism in Asian Patients with Cancer

Previous cohort studies had demonstrated that Asian patients with cancer have

significant reduced risk of VTE compared with Caucasian patients with cancer.^6,7,51

However, population-based epidemiological studies in Asian demonstrated a yearly

increased incidence of VTE in Asians.⁸ Recently, several studies focused on VTE

among cancer patients in Asian populations had been published. Incidence of VTE in

multiple myeloma, gastric cancer, colorectal cancer, advanced pancreatic cancer, diffuse

large B-cell lymphoma, and cholangiocarcinoma ranged from 3.7% to 10.6% (Table

2.9).^12-18

VTE incidence among patients with multiple myeloma receiving thalidomide- or

lenalidomide- based combination therapy was 5.3%, which is lower than that reported

in Western countries (10 to 20%).¹³ In a retrospective study among patients with

colorectal cancer based on database of Seoul National University Bundang Hospital

found that the 2-year cumulative incidence of VTE was 3.6%. The 2-year cumulative

incidence of DVT/PE ranged from 0.3%, 0.9%, 1.4% and 6.4% in stages 0-1, 2, 3, and 4,

respectively.¹⁵ Development of DVT/PE but not intra-abdominal venous thrombosis was

related to increased mortality in both patients with loco-regional and metastatic disease.

Similar finding was shown in another study in patients with gastric cancer.¹⁴ Although

Asian patients with loco-regional malignant disease had lower VTE incidence than

(45)

30

Western populations, the VTE incidence is similar among patients with distant

malignant disease. The incidence of VTE among Japanese patients with DLBCL was

reported to be comparable with that in Caucasian populations.¹⁶ On the other hand, the

risk of postoperative VTE was much lower than in Caucasian patients (~0.2%) but

further investigations are needed to confirm this finding.^14,15

(46)

31

Table 2.9 Cohort studies of incidence of venous thromboembolism in patients of specified cancer site among Asian population

patients

VTE event (%) Korea

Oh et al. (2008)¹²

Electronic medical records database of Seoul National University Bundang Hospital

Patients with advanced pancreatic cancer

Objectively confirmed VTE 132 5.3

Korea

Koh et al. (2010)¹³

Korean multiple myeloma registry

Patients received thalidomide for multiple myeloma

Objectively confirmed symptomatic VTE

360 3.9

Korea

Lee et al. (2010)¹⁴

Patients with gastric cancer

Objectively confirmed extremity venous thrombosis, PE and intra-abdominal thrombosis

2,085 3.8*

Korea

Choi et al. (2011)¹⁵

Patients with colorectal cancer

Objectively confirmed extremity venous thrombosis, PE and intra-abdominal thrombosis

2,006 3.6*

Japan

Yokoyama et al. (2011)¹⁶

Medical records database of Keio University Hospital

Patients with diffuse large B-cell lymphoma

Objectively confirmed symptomatic VTE

142 10.6

Korea

Kang et al. (2012)¹⁷

Medical records database of Asan Medical Center, Seoul

Patients with advanced gastric cancer

Objectively confirmed DVT/PE 3,095 4.9*

Korea

Jeon et al. (2012)¹⁸

Medical records database of Pusan National University Hospital

Patients with

cholangiocarcinoma

Objectively confirmed VTE (including intra-abdominal thrombosis)

273 3.7

* 2-year cumulative incidence

(47)

32

Chapter 3 Study Objective

Using the administrative claims data from the NHI database, the goal of this

population-based cohort study were:

(1) to explore the incidence date and timing of VTE,

(2) to identify the risk factors for VTE,

(3) to describe the clinical characteristics and treatment pattern of VTE,

(4) to examine the incidence of recurrent VTE and bleeding complications during

long-term treatment of VTE among cancer patients.

(48)

33

Chapter 4 Materials and Methods

4.1 Data Source

This population-based cohort study was based on Longitudinal Health Insurance

Database (LHID) of National Health Insurance research database (NHIRD) in Taiwan.

The NHI program was organized by the government and operated by Taiwan’s Bureau

of the NHI. This mandatory, single-payer health insurance was launched in 1995, and

has covered over 99% of Taiwan’s population (approximately 23 million residents) and

contracted with 97% of hospital as well as clinics throughout the nation. It provides comprehensive beneﬁts, including inpatient care, ambulatory care, dental care, and

prescription drug coverage, to all beneﬁciaries. Registration datasets and claims

databases of all beneficiaries in the NHI program have been maintained since 1997 and

offer an excellent opportunity to conduct studies.^89,90

This study uses LHID 2000, LHID 2005 and LHID 2010 as data source. LHID

2000, LHID 2005 and LHID 2010 contain all the original claim data of 1,000,000

beneficiaries randomly sampled from the year 2000, 2005, and 2010 Registry for

Beneficiaries (ID), respectively. All traceable personal identifiers are removed from the

database to protect patient confidentiality.⁹⁰ The databases used in this study included

all inpatient and outpatient medical claims from January 1, 1999 to December 31, 2009.

(49)

34

4.2 Study Population and Study Outcomes

4.2.1 Study Cohort

Our study population included newly diagnosed cancer patients who have been

hospitalized with a primary diagnosis of malignant disease, identified by International

Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code

(ICD-9-CM codes: 140.x-208.xx) between January 1, 2001 and December 31, 2008.

Diagnoses in NHI research databases are coded using the ICD-9-CM coding scheme

since 2000.⁸⁹ This time frame allowed for retrieving at least 1 year of baseline data prior

to cancer diagnosis and up to 1 year of follow up after cancer diagnosis.

Major categories of malignant diseases that were included and their ICD-9-CM

diagnosis codes were shown in Table 4.1. We used the year 1999 as a run-in year to

identify incident cases of malignant diseases. The date when the patient was first

hospitalized with a primary diagnosis of malignant disease was defined as the index

date. Patients were excluded from this study if their genders were unknown or they had

more than one primary diagnosis of malignant diseases at index date, for their cancer

sites cannot be categorized.

(50)

35

Table 4.1 ICD-9-CM codes of inclusion diagnosis

Cancer site ICD-9-CM codes

Head & neck cancer 140.x-149.x, 160.x-161.x

Esophageal caner 150.x

Stomach cancer 151.x

Colorectal cancer 153.x-154.x

Liver cancer 155.x

Pancreas cancer 157.x

Other abdominal cancers 152.x, 156.x, 158.x, 159.x

Lung cancer 162.x-163.x

Sarcoma 170.x-171.x

Skin cancer 172.x-173.xx

Breast cancer 174.x-175.x

Endometrial cancer and cervical cancer 179-182.x

Ovarian cancer 183.x

Prostate cancer 185

Testicular cancer 186.x

Bladder cancer 188.x

Renal cancer 189.x

Brain cancer 191.x-192.x

Thyroid cancer 193

Non-Hodgkin’s lymphoma 200.xx, 202.xx

Hodgkin’s lymphoma 201.xx

Multiple myeloma 203.xx

Leukemia 204.xx-208.xx

靜脈血栓栓塞症於癌症病人之流行病學與治療現況

國立臺灣大學醫學院臨床藥學研究所 碩士論文

Graduate Institute of Clinical Pharmacy College of Medicine

National Taiwan University Master Thesis

靜脈血栓栓塞症於癌症病人之流行病學與治療現況 Epidemiology and Clinical Profile of Venous

Thromboembolism in Cancer Patients

周丹薇 Tan-Wei Chew

指導教授：蕭斐元 博士 高純琇 博士

Advisor: Fei-Yuan Sharon Hsiao, Ph.D.

Churn-Shiouh Gau, Ph.D.

中華民國 101 年 7 月

July, 2012

謝辭

中文摘要

Abstract

Contents

List of Figures

List of Tables

Chapter 1 Introduction

Chapter 2 Literature Review

2.1 Venous Thromboembolism

2.1.1 Overview of Venous Thromboembolism

2.1.2 Epidemiology of Venous Thromboembolism

2.1.3 Risk Factors for Venous Thromboembolism

2.1.4 Complications of Venous Thromboembolism

2.1.5 Clinical Presentations of Venous Thromboembolism

2.1.6 Diagnosis of Venous Thromboembolism

2.2 Venous Thromboembolism in Patients with Cancer

2.2.1 Overview

2.2.2 Epidemiology of Cancer-related VTE

2.2.3 The Pathogenesis of VTE in Cancer

2.2.4 Risk Factors for Cancer-related VTE

2.2.5 Consequences of Cancer-related VTE

2.2.6 Treatment of Venous Thromboembolism in Cancer Patients

2.2.7 Prevention of Venous Thromboembolism in Cancer Patients

2.2.8 Venous Thromboembolism in Asian Patients with Cancer

Chapter 3 Study Objective

Chapter 4 Materials and Methods

4.1 Data Source

4.2 Study Population and Study Outcomes

4.2.1 Study Cohort

國立臺灣大學醫學院臨床藥學研究所碩士論文

指導教授：蕭斐元博士高純琇博士