靜脈血栓栓塞症於癌症病人之流行病學與治療現況

Abstract

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：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。

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 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 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.