| 摘要: | 研究背景：台灣有 25.3%的男性(血中尿酸值>7.0 mg/dl)與 16.7%的女性(血中尿酸值>6.0 mg/dl)其血液尿酸值大於標準值。雖然有研究指出，高尿酸血症是心血管疾病的獨立風險因子，但也有研究質疑血中尿酸值只能當作心血管風險的生物指標。Allopurinol 是目前常見的長期尿酸降低治療藥物，相關的研究指出；allopurinol 能
減少氧化壓力並減少內皮功能障礙，進而降低心血管疾病的發生。促進尿酸排泄類藥物，如 benzbromarone、probenecid 及 sulfinpyrazone，則被認為僅能促進尿酸排泄。
研究目的:本研究嘗試使用次級資料庫，探討以族群為基礎使用促尿酸排泄或抑制尿酸合成之尿酸降低治療後，與心血管疾病風險之關係，並進而探討尿酸降低治療後，血中尿酸值高低及使用治療之每日劑量，與心血管疾病風險之關聯性。
材料方法：本研究為兩部分之長期追蹤世代研究。第一部分為 2005 年承保抽樣百萬歸人檔，使用 1997 年至 2009 年總計 13 年的健保申請資料庫。952,551 位痛風或高尿酸血症病患中，排除混用兩種降尿酸藥物、有過去心血管疾病病史、年齡小於 18 歲及性別不清楚之病人，並根據年齡±2.5 歲、相同性別與痛風診斷±30 天，進行 1:2:4 配對後，抑制尿酸合成暴露組(allopurinol 組)有 4,900 人、促進尿酸排泄暴露組(uricosurics 組)有 9,800 人與沒有使用藥物暴露組(non-treated 組)有 19,596 人，可以進行不同藥物暴露及每日暴露藥量對於心血管疾病發生風險相關性之探討。第二部分為成人預防保健成果檔與 2005 至 2011 年之全民健保資料庫全檔之勾稽。2,889,603 位痛風或高尿酸血症病患中，排除兩種長期尿酸降低治療皆使用、有過去心血管疾病病史、年齡小於 35 歲及性別不清楚之病人，並根據年齡±2.5 歲、相同性別與痛風診斷±30 天，進行 1:2:4 配對後，抑制尿酸合成暴露組(allopurinol 組)有14,713 人、促進尿酸排泄暴露組(uricosurics 組)有 29,426 人與沒有使用藥物暴露組(non-treatede 組)有 58,820 人，可以進行血中尿酸值濃度對於心血管疾病發生風險相關性之探討。連續性變項以 ANOVA 做檢定，類別變項則以 χ 2 或 Fisher exact 檢定進行分析。另外使用 Cox proportional hazards model 評估藥物暴露情況與心血管疾病
之死亡風險比(Hazard ratio)。並進行次族群分層分析，探討控制變項分層後與心血管疾病之關聯性。
結果：無論是何種藥物暴露，其心血管疾病風險皆比非暴露組顯著較高(HR 皆> 1 , p<0.05)，但經校正共病症、身體質量指數、嚼檳榔與否後，uricosurics 組的心血管疾病風險與非暴露組無顯著差異。在針對有三種或以上共病症的次族群進行分層分析後，與非暴露組且血中尿酸值大於 9 mg/dl 者相比，非暴露組與 uricosurics組中尿酸較低者有顯著的保護趨勢(HR 皆< 1 , p<0.05)，不過在沒有任何共病症的病患中沒有發現類似趨勢。兩組藥物暴露使用每日使用之高劑量與低劑量相比，皆會保護心血管疾病發生風險(HR 皆< 1 , p<0.05)，但校正共病症與暴露總天數後，兩組雖皆有保護趨勢但未達顯著。老年人或女性控制血中尿酸值濃度更能保護心血管疾病。
結論：本研究結果顯示，雖然尿酸對於心血管疾病的影響在較健康的民眾不會比其他心血管疾病風險因子更強烈，但在健康狀況不佳的病患中，更該重視尿酸這個議題。高心血管疾病發生風險的高尿酸血症及痛風病患應使用尿酸降低治療血中尿酸值濃度，以防止後續心血管疾病發生的風險。
Background: There are 25.3% male (with the value of blood uric acid > 7.0 mg/dl) and 16.7% female (> 6.0 mg/dl) whose value of serum uric acid is abnormal in Taiwan. Several evidences showed hyperuricemia is an independent risk factor of cardiovascular disease (CVD), however, other studies challenged that uric acid can only be a biomarker to CVD. Allopurinol is a popular medicine to reducing serum uric acid level. Some
studies indicated allopurinol reduced the oxidative stress, disordered the endothelial function and decreased the incidence of CVD. Uricosuric drugs such as benzbromarone,
probenecid and sulfinpyrazone, is considered only promote uric acid excretion.
Objective: We intend to investigate the association between two kinds of the uric acid-lowering therapy and the risk of CVD in a population-based study. And further we investigate the association between the level of blood uric acid, and the rick of CVD after the uric acid-lowering therapy.
Materials and methods: There are two part in this longitudinal study. First is a study using claims data of National Health Insurance Research Database (NHIRD) of Longitudinal Health Insurance Database 2005 (LHID2005) from 1997 to 2009.There
included 952,551 patients with gout and hyperuricemia. Then, we excluded the patients who use both uric acid-lowering therapies, have the history of CVD, aged under 18 and
have unknown gender. A 1 to 2 to 4 matching ratio with age ± 2.5 years, same sex and diagnosis index date ± 30 days. Finally, there are 4,900, 9,800 and 19,596 patients in allopurinol, uricosurics and non-treated group, respectively. The second part is a study using the database of Adult Health Examination compare with National Health Insurance Research Database from 2005 to 2011. There are 2,889,603 patients with gout and
hyperuricemia. We excluded the patients who use uric acid-lowering therapies, have the history of CVD, aged under 35 and have unknown gender. A 1 to 2 to 4 matching ratio with age ± 2.5 years, same sex and diagnosis index date ± 30 days. Finally, there are 14,713, 29,426 and 58,820 patients in allopurinol, uricosurics and non-treated group, respectively. To compare the difference between 3 groups, ANOVA is used for continuous
variable and chi-square test or fisher exact test are used for categorical variable. The stratified Cox proportional hazards model is used. A stratified analysis was used to
investigate the relationship in CVD after stratify control variables.
Result: Whether allopurinol or uricosurics group, the hazard ratio (HR) of CVD are both significantly higher than non-treated group (both HR > 1 , p<0.05), but there are no significant after adjustment of the comorbidities, body mass index (BMI) and chewing betel nut. In the analysis focused on the patients who have three or more comorbidities, both in non-treated and in uricosurics group who have <9 mg/dl of serum uric acid are
protective (both HR< 1, p<0.05) to CVD, compared with the non-treated subjects whose serum uric acid level greater than 9 mg / dl. The subjects taking allopurinol or uricosurics
compared with high daily dosage, they protect the onset risk of CVD (both HR > 1 , p<0.05). However, it have no significant difference after adjusting comorbidities and total days of the exposure. The elderly or women both in non-treated and in uricosurics group who have <9 mg/dl of serum uric acid are protective to CVD.
Conclusion: This study demonstrated that the impact of serum uric acid level for CVD is less strong than other risk factors of CVD in healthy people. But in the patients who have comorbidities, the impact of uric acid-lowering therapy is influenced. Patients with gout and hyperuricemia who have high CVD rick of should take the uric acid-lowering therapy. |
