||The risk of hormone therapy in postmenopausal women in Taiwan
||Institute of Clinical Pharmacy and Pharmaceutical sciences
oral hormone therapy
研究方法:本研究使用台灣的全民健康資料庫，分別進行回溯性研究。深層靜脈栓塞的診斷在2001年和2002年確定的第一世代研究有5,347成年患者（2,463人，46.1％）。我們計算了深層靜脈栓塞的發生率及復發率。我們還進行了重疊病例對照研究（n = 3576），利用條件邏輯性回歸分析估計深層靜脈栓塞復發和潛在的深層靜脈栓塞危險因素的的關聯性。再進行1998年至2008年回溯性研究。首先，分別先建立年齡≧50歲的使用過和未使用口服賀爾蒙激素治療兩個婦女世代研究群。經過傾向分數配對後，計算使用過和未使用口服賀爾蒙激素治療婦女在追蹤2年得到深層靜脈栓塞的發生率。利用回歸分析停經後婦女發生深層靜脈栓塞之危險因素。在重疊病例對照研究中，定義病例組為研究期間發生的深層靜脈栓塞的個案，以年齡及納入時間配對出1:20的對照組，利用條件邏輯性回歸估計深層靜脈栓塞和不使用、現在和過去使用口服賀爾蒙激素治療之相關危險性。同時進行次組分析驗證本研究結果。
研究結果:深層靜脈栓塞粗發生率分別為15.9每10萬人年，復發率為5.1％每人年。在11,566人年的隨訪期間，6、12、24、36、和47個月的深層靜脈栓塞復發累積率分別為6.7％，9.4％，12.4％，13.9％和14.4％。條件邏輯性回歸分析發現，曾經發生深層靜脈栓塞（OR 1.71，95％CI 1.32-2.16）或惡性腫瘤（OR 1.64，95％CI 1.26-1.99），主要下肢創傷（OR 2.76，95％CI 1.82-4.52），嚴重的神經系統疾病（OR 1.43，95％CI 1.12-1.84），或接受重大手術（OR 4.57，95％CI 1.72-12.50）與深層靜脈栓塞復發的風險較高。在停經後婦女中分別得到394261位口服賀爾蒙激素患者和477187位無使用口服賀爾蒙激素患者。平均年齡分別為未使用口服賀爾蒙激素患者（66.8 ± 16.3歲）和口服賀爾蒙激素患者（63.4 ± 14.4）（P <0.001）。我們觀察到未使用口服賀爾蒙激素患者有較高比例的，包括癌症，陳舊性心肌梗塞和腦血管事件的相關合併症。使用口服賀爾蒙激素患者和未使用賀爾蒙激素患者2年的深層靜脈栓塞發生率分別為6.2與6.7 每10,000人年（調整後的HR 0.997，95％CI 0.88-1.13）。傾向分數匹配後，使用口服賀爾蒙激素患者和未使用賀爾蒙激素患者2年的深層靜脈栓塞發生率分別為6.1與4.7每10,000人年（調整後HR 1.29，95％CI 1.08-1.547）。回歸分析顯示，年齡，惡性腫瘤，心血管疾病，靜脈曲張，近期大手術皆為停經後婦女發生靜脈血栓栓塞的獨立危險因素。在重疊病例對照研究，其中4140位病例組(停經後婦女發生靜脈血栓栓塞)並且配對出82800位控制組(停經後婦女無靜脈血栓栓塞)。調整後發現和沒有使用過口服賀爾蒙激素相比，目前正使用的口服賀爾蒙激素的患者具有較高發生深層靜脈栓塞的風險(OR 2.36，95％CI 1.99至2.80）、最近使用也具有較高的風險（OR 1.43，95％CI 1.12-1.83）以及過去使用無明顯的風險（OR 1.06，95％CI 0.90-1.25）。經過條件式邏輯斯迴歸模式分析得到口服賀爾蒙激素、靜脈曲張、心臟衰竭、高血壓、接受重大手術都會增加停經後婦女有較高的靜脈血栓栓塞風險。
Background: The incidence of VTE in Asians was generally lower compared to Caucasians. Hormone therapy (HT) is a definite risk factor of VTE in Western studies. However, information on the incidence and risk factors of VTE in postmenopausal women receiving HT in Asia is scarce.
Objectives: We aimed to investigate VTE incidences and evaluate the VTE risk in postmenopausal women receiving HT.
Methods: We used the Taiwanese National Health Insurance claims databases to establish several cohorts. The first cohort identified 5,347 adult patients (2,463 men, 46.1%) with VTE diagnosed in 2001 and 2002. We calculated the crude incidence of VTE and its recurrence. We also conducted a nested case-control study (n=3576) among this population to estimate the association between VTE recurrence and exposure to potential VTE risk factors by conditional logistic regression. Then, we established another two cohorts (HT and non-HT users) including postmenopausal women aged ≧50 years between 1 January 1998 and 31 December 2008. The non-HT users were matched based on age (±2 years) and enrolled year. We calculated the 2-year incidence of VTE in postmenopausal women receiving HT or not, respectively. Among cohorts, HT users and non-HT users were matched 1:1 based on propensity score matching again. Cox regression hazard model was used to identify risk factors of VTE in the cohorts. Using a nested case–control approach, all incident cases of VTE occurring during the study period were identified and matched with up to 10 controls selected from the cohort members. Adjusted odds ratios (OR) of VTE with non-use, current and past use of oral HRT were estimated using conditional logistic regression.
Results: The crude incidence of VTE was 15.9 per 100,000 person-years and its recurrence was 5.1% per person-year. During 11,566 person-years of follow-up, the cumulative rates of VTE recurrence at 6, 12, 24, 36, and 47 months were 6.7%, 9.4%, 12.4%, 13.9%, and 14.4%, respectively. By conditional logistic regression, histories of VTE or cancer, major extremity trauma, serious neurologic diseases, or receiving major surgery were associated with higher risks of VTE recurrence. We identified 394261 HT users and 477187 non-HT users in the cohorts. The mean age was elder in non-HT (66.8 ± 16.3 years) than HT users (63.4 ± 14.4 years) (P<0.001). We observed higher percentages of underlying comorbidities in non-HT users including cancer, old myocardial infarction, and old cerebrovascular events. The 2-year VTE incidence was 6.2 versus 6.7 per 10,000 patients-years (adjusted HR 0.997, 95% CI 0.88-1.13) in HT and non-HT users, respectively. After propensity score matching, the VTE incidence was 6.1 versus 4.7 per 10,000 patients-years (adjusted HR 1.29, 95% CI 1.08-1.547) in HT and non-HT users, respectively. Cox regression hazard model showed that elder age, malignancy, cardiovascular diseases, varicose veins, and recent major surgery were independent risk factors for VTE in postmenopausal women. In the nested case-control analysis, we included 4140 cases of VTE matched with 82800 controls. The adjusted odds ratios of VTE associated with current use of oral HT was 2.36 (95% CI 1.99 to 2.80) relative to no use. The risk of VTE was also increased with recent use of oral HT (ORs 1.43; 95% CI, 1.12–1.83) and remote use (ORs 1.06; 95% CI, 0.90–1.25) relative to no use. By conditional logistic regression, oral HT users, histories of varicose veins, heart failure, hypertension, and receiving major surgery were associated with higher risks of VTE events.
Conclusions: The incidence of VTE is lower in the Taiwanese population than in Caucasians. Most VTE recurrences occur within 12 months, but continue to occur beyond one year. The VTE recurrences are associated with malignancy, history of VTE, and major surgery after a previous VTE. Although the incidence of VTE was low in Taiwanese postmenopausal women, oral HT was still associated with an increased risk of VTE. Therefore, physicians should take care of prescribing oral HT to postmenopausal women with other potential VTE risk factors.
Chapter 1. Introduction 1
1.1 Statement of Problem 1
1.2 Specific Aims 2
1.3 Significance of This Study 3
Chapter 2. Literature Review 5
2.1 Introduction of Venous Thromboembolism 5
2.2 Risk Factors of Venous Thromboembolism 6
2.3 Survival and Recurrence after Venous
2.4 Prevention of Venous Thromboembolism 7
2.5 Hormone Therapy and Risk of Venous
2.6 Summary of Literature Review 12
Chapter 3. Objectives and hypothesis 14
Chapter 4. Methods 15
4.1 Epidemiology of Venous Thromboembolism in
4.1.1 Study design 15
4.1.2 Data source and material 15
4.1.3 Case definition and exclusion criteria 16
4.1.4 Comorbid diseases and potential risk factors
of VTE 16
4.1.5 Statistical analysis 17
4.2 Hormone Therapy and Risk of Venous
4.2.1 Study design 18
4.2.2 Data source and material 18
4.2.3 Potential confounding variables of VTE 18
4.2.4 Case definition and exclusion criteria 19
4.2.5 Hormone therapy exposure 19
4.2.6 Statistical analysis 20
Chapter 5. Results 22
5.1 Epidemiology of Venous Thromboembolism in
5.1.1 Crude Age- and Gender-specific Incidence 22
5.1.2 Cumulative Rates of VTE Recurrence 23
5.1.3 Risk Factors of VTE Recurrence 23
5.2 Hormone Therapy and Risk of Venous
5.2.1 Characteristics and VTE incidence in
postmenopausal women 24
5.2.2 Predictors of VTE in postmenopausal women
5.2.3 Baseline clinical characteristics in the
nested case-control study 26
5.2.4 Association of HT and VTE 26
5.2.5 Sensitivity Analysis 26
Chapter 6. Discussions 28
6.1 Epidemiology of Venous Thromboembolism in
6.2 Hormone Therapy and Risk of Venous
Chapter 7. Strength and Clinical Implication 33
7.1 Epidemiology of Venous Thromboembolism in
7.2 Hormone Therapy and Risk of Venous
Chapter 8. Limitations 34
8.1 Epidemiology of Venous Thromboembolism in
8.2 Hormone Therapy and Risk of Venous
Chapter 9. Conclusions 36
Published papers 75
Appendix I ICD-9-CM for covariance and procedure/surgery
Appendix II Ethical approval documentation for current
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