- 學位論文
高血壓患者使用Thiazide類藥物與整體骨折發生率風險的關聯性研究：一個以臺灣人口為基礎的世代研究
Association of thiazide use in patients with hypertension with overall fracture risk:A population-based cohort study
摘要
研究目的 隨著全球人口老齡化，肌肉損失和骨質疏鬆症成為一個更重要的問題，因為骨質疏鬆的骨頭即使是輕微的碰撞也很容易骨折。骨質疏鬆性骨折是急診科很常見的損傷之一。 長期以來，thiazide類利尿劑被廣泛用作抗高血壓藥。thiazide類藥物被定義為三線抗高血壓藥，因為其降低血壓的效果不如血管緊張素轉換酶抑製劑或血管緊張素 II 受體拮抗劑。thiazide類藥物抑制曲折的腎遠曲小管中的 Na + / Cl 協同轉運蛋白 (NCC)。 NCC 促進鈉從遠端小管重新吸收到間質。隨著鈉重吸收的減少，使用會急遽地導致尿液中液體增加的損失，從而導致細胞外液（ECF）和血漿量的減少。這種容量損失導致靜脈回流減少、腎素釋放增加、心輸出量減少和血壓降低。除了降低血壓之外，thiazde類藥物有增加鈣離子回收調節的作用，進而使身體的鈣離子增加，儲存於骨頭，達到增加骨密度的效果。 我們的研究主要目的為探討使用thiazide類藥物是否可以減低在高血壓患者族群中的骨折機會。 骨質疏鬆性骨折亦是停經圍期或停經後婦女常見的併發症之一。 我們的第二個目標是探討使用thiazide類藥物是否可以預防停經圍期或停經後婦女的骨折。 研究方法及資料 我們使用作為國家健康保險研究數據庫 (NHIRD) 子集的 2000 年縱向健康保險數據庫 (LHID)，將 2002 年至 2016 年期間確診並接受抗高血壓治療的高血壓患者納入其中。患者進一步分為兩組 基於thiazide類藥物使用者和非thiazide類藥物使用者的類別。 研究事件被定義為骨折的診斷。 採用多 Cox 回歸模型的多變量分析來分析數據。 進一步進行傾向得分匹配（PSM）以減少由於混雜變量引起的偏差。 研究結果 研究組共納入 18593 名 高血壓且使用thiazide類藥物患者，另外 74372 名患者在索引日期時性別年齡（±1 歲）匹配，納入對照組。在按性別、年齡、城市化、收入和合併症進行 1:1 PSM 匹配後，得到有 18,483 個高血壓患者且使用thiazide類藥物及18,483個高血壓患者且不使用thiazide類藥物。 在 PSM 後，性別年齡匹配thiazide類藥物組和非thiazide類藥物組的骨折發生率密度（每 1000 人月）分別為 1.83（95% CI：1.76-1.90）和 1.97（95% CI：1.94-2.01） (95% CI: 1.76-1.89) 和 1.99(95% CI: 1.92-2.06), thiazide類藥物的調整後風險比為 0.926(95% CI: 0.879-0.976)。 Kaplan-Meier 生存分析顯示，高血壓組 With-Thiazide（P=0.0012）的累積骨折發生率顯著降低。 多重Cox 迴歸分析骨折的調整風險比（aHR），與未使用thiazide類藥物相比，使用thiazide類藥物的風險顯著降低，aHR為0.92（95％CI：0.87-0.97）。 結論與建議 我們的研究發現使用thiazide類藥物可以預防骨折。在考慮使用抗高血壓藥物時，如果患者有骨質疏鬆骨折的風險，thiazide類藥物可能是一種選擇。 thiazide類藥物是非常常見的且用於控制血壓的抗高血壓藥物之一，同時也可以預防骨質疏鬆骨折。通過群組次級分析，我們亦發現40-50歲區間的女性使用thiazide類藥物對預防骨折有好處。這可以是停經圍期婦女使用高血壓藥物的一個考慮因素。
並列摘要
Objective Four main classes of medications are used in combination therapy for the treatment of hypertension: thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs). Physicians choose antihypertensive for the patient according to the underlying diseases or contraindication. Thiazide diuretics have been widely used as antihypertensive agents for a long period of time. Thiazides inhibit the Na + / Cl cotransporter (NCC) in the convoluted renal distal tubule. The NCC facilitates the re-absorption of sodium from the distal tubules to the interstitium, which leads to a decrease in extracellular fluid (ECF) and plasma volume. In addition to the effect on reducing blood pressure, thiazides control calcium homeostasis and increase bone density. We hypothesize that the use of thiazide in hypertension patients could reduce the risk of overall fracture. Osteoporotic fracture was one of common complication in perimenopausal or postmenopausal women. Our second goal is to find whether the use of thiazide could prevent fracture in perimenopausal or postmenopausal women. Material and Methods We used the National Health Insurance Research Database (NHIRD), a system that Taiwan adopted in 1995, to include patients of hypertension with diagnosis and accepted antihypertensive treatment between 2002 to 2016. The patient further categorized into two groups based on category of the thiazide user and non-thiazide user. The study event was defined as the diagnosis of fracture. Multivariate analysis with a multiple Cox regression model was applied to analyze the data. Propensity score match (PSM) was further performed to reduce the bias due to confounding variables. Results A total of 18620 patients with HT with-thiazide were included in the study group, and an additional 74372 individuals were sex age (±1 years old) matching at index date enrolled in the control group. After 1:1 PSM matching by sex, age, urbanization, income, and comorbidities yielded 18,483 with-Thiazide and Without-Thiazide. Incidence density of fracture (per 1000 person months) was 1.83 (95% CI: 1.76-1.90) and 1.97(95% CI: 1.94-2.01) in the sex age matching with-Thiazide and without-Thiazide cohorts, after PSM were 1.82(95% CI: 1.76-1.89) and 1.99(95% CI: 1.92-2.06), and the adjusted Hazard Ratio for with-Thiazide was 0.926(95% CI: 0.879-0.976). A Kaplan–Meier survival analysis revealed a significantly lower cumulative incidence of fracture in the With-Thiazide (log rank test; P=0.0012) of hypertension group. Multiple cox regression showed the adjusted hazard ratio (aHR) of fracture, with-Thiazide has a significantly reduced risk compared with without-Thiazide, the aHR was 0.92 (95% CI: 0.87-0.97). Conclusion and Suggestion Our study indicated use of thiazide could prevent fracture. When consideration of using antihypertensive agent, thiazide can be one of choice if patient had risk of fragile fractures. By use of subgroup analysis, we found that woman in age of 40’s using thiazide had benefit on fracture prevention.
參考文獻
延伸閱讀
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