- 學位論文
抗血小板凝集藥物於台灣特殊族群使用之療效及安全性探討
Investigation on Effectiveness and Safety of Antiplatelet Drugs in Taiwan Special Population
摘要
研究背景:目前於臨床上最常使用之抗血小板凝集藥物為aspirin及clopidogrel。然而，部分病人服用aspirin和clopidogrel後，卻無法達到良好的血小板凝集抑制效果，則稱之為aspirin和clopidogrel抗阻性。以目前研究顯示aspirin和clopidogrel之抗阻性成因可分為外因性及內因性，而外因性因素中更包含了腸胃道疾病及肝腎功能疾病等。根據aspirin和clopidogrel之藥物動力學可發現，肝臟及腎臟皆對此兩種藥物有所影響，但目前在臨床上對於肝腎功能異常或其他血管性病人於使用抗血小板凝集藥物仍有非常大的爭議，如不穩定之血液動力學、藥物治療效果未明及副作用。 研究目的:本研究目的為研究台灣特殊族群病人使用抗血小板凝集藥物之臨床治療效果及安全性。因此，本研究分為三部份分別探討1)以首次因缺血性血管性疾病住院的肝硬化病人為例，探討肝硬化病人使用抗血小板凝集藥物，對於再中風、死亡或腸胃道出血之風險是否增加。2) 因缺血性腦中風住院之透析病人為納入族群，探討透析病人使用抗血小板凝集藥物，對於再中風、心肌梗塞、死亡或出血之風險是否增加。3) 探討低劑量aspirin使用於胸或腹主動脈瘤病人是否能有效緩解其主動脈瘤惡化程度及死亡率。 研究方法: 本研究採用全民健康保險資料，分別進行回溯性研究。第一部份及第二部份採用重大傷病病人就醫資料篩選研究對象及分析。經篩選後成為觀察之對象在針對第一次發生缺血性腦中風之病人進行篩選，肝硬化病人產生缺血性腦中風須介於 1997-2006年間，而透析病人則須介於 1998-2006年間。於追蹤期間，本研究經由評估病人是否使用抗血小板凝集藥物進行用藥及未用藥分組，並進行臨床效果及風險分析。第三部份採用2000年承保抽樣歸人檔資料進行主動脈瘤病人篩選(病人產生主動脈瘤須介於 1999-2006年間)，並評估病人於追蹤期間是否使用低劑量aspirin進行分組用藥及未用藥分組，探討結果之風險是否相同。本研究採用Cox proportional hazards model進行分析，並將抗血小板凝集藥物之使用做為時間依賴共變相(Time-dependent variable)。 研究結果與討論:於第一部份共納入1,180位肝硬化且患有缺血性腦中風之個案，而使用aspirin之病人相對於未使用者能有效減少8.5% 再栓塞或死亡之風險 (hazard ratio (HR): 0.915; 95% confidence interval (CI): 0.872–0.960)且未增加腸胃道出血之風險(HR:0.998; 95% CI: 0.946–1.052);而clopidogrel未能顯示預防之效果，但也未增加腸胃道出血風險。第二部分納入1,936位透析且患有缺血性腦中風病人，根據結果可得知aspirin之使用相對於未使用者能減少32.9%再栓塞或死亡之風險 (HR: 0.671; p<0.001)且未增加腸胃道出血之風險(HR: 0.885; p=0.291);而clopidogrel亦未能顯示治療效果(HR: 0.933;p=0.497)，但也未增加腸胃道出血風險(HR: 0.827; p=0.360)。第三部分納入287位主動脈瘤病人，並將之分為235位腹主動脈瘤及52位胸主動脈瘤。經分析後發現aspirin的使用無法有效減少腹主動脈瘤之疾病惡化(HR: 1.000; 95% CI: 0.994 to 1.005)或胸主動脈瘤(HR: 1.010 ;95% CI: 0.994 to 1.026)。 結論: 於健保資料庫分析中抗血小板凝集藥物使用於肝硬化或透析病人且患有缺血性腦中風之病人，aspirin及clopidogrel並未顯示出相同治療果效，但皆未提高腸胃道及相關出血副作用。另一方面，雖低劑量aspirin未能顯示期減少主動脈瘤之效果，但也未增加其相關風險。而本研究目前持續多方面探討，將評估方式應用到不同栓塞性疾病，並增加其他效果評估指標。因此透過多方面探討抗血小板凝集藥物於台灣族群使用之效果評估上，於未來將合併探討臨床上特殊族群病人使用抗血小板凝集藥物後之血小板凝集狀態及探討病人在臨床治療效果是否受其特殊疾病因素影響而減低其治療效果。最後，希望建置有效的治療對策與指引並能提供臨床及政策上有效且對病人有益之醫療決策。
並列摘要
Background: Aspirin and clopidogrel have been used for antiplatelet therapy in patients with cardiovascular and cerebrovascular diseases, particularly patients with thrombus diseases or at high risk of vascular diseases. Recently, the reasons of resistance to aspirin and clopidogrel, which result in variability toward antiplatelet drug responses, were discussed. Gastrointestinal, liver, kidney, or vascular diseases are some of the factors that lead to increased resistance to aspirin and clopidogrel. On the other hand, compared with the overall population, most patients with cirrhosis and chronic kidney diseases (severe clinical diseases) have hemodynamic instability. Moreover, data on antiplatelet therapy for disease prevention in these special populations are limited. Aim: The purpose of the current study was to use the National Health Insurance Research Database (NHIRD) to investigate the effectiveness and safety of antiplatelet drugs for special populations: 1) to study the effectiveness and safety of antiplatelet drugs (aspirin and clopidogrel) in the prevention of recurrent ischemic stroke (IS) and mortality in patients with liver cirrhosis, during the study period after the first-time IS; 2) to estimate the effectiveness and safety of the antiplatelet drugs aspirin and clopidogrel for the prevention of recurrent IS in patients with end-stage renal disease (ESRD) undergoing renal replacement therapy during long-term follow-up after the first-time IS; 3) to investigative utilization of low-dose aspirin in patients with aneurysm. We aimed to assess the association between low-dose aspirin exposure and disease progression and safety in patients with abdominal aortic aneurysm (AAA)/thoraco-abdominal aortic aneurysm (TAAA) and thoracic aortic aneurysm (TAA). Method: We first identified cases of liver cirrhosis or ESRD with dialysis from NHIRD. Antiplatelet therapy was administered as follow-up in patients who had experienced a first IS between 1997 and 2006 in patients with liver cirrhosis, and in patients with ESRD who had experienced a first IS between 1998 and 2006. Primary outcomes, including death and hospital readmission for stroke, and secondary outcomes, including death, stroke, or gastrointestinal or related bleeding, were examined. Second, we identified aortic aneurysm cases from NHIRD, and used time-dependent methods to determine whether the use of low-dose aspirin reduced the risk of all causes of death and exacerbation. Low-dose aspirin was administered as follow-up to patients who had experienced first aortic aneurysms between 1999 and 2006. Results and discussions: Our study identified 1,180 patients with liver cirrhosis who experienced a first IS. According to a time-dependent analysis, the hazard ratio (HR) for primary outcomes in patients treated with aspirin was 0.915 (95% CI: 0.872–0.960). In secondary outcomes, HR for readmission for stroke was 0.904 (95% CI: 0.835–0.977) and that for gastrointestinal bleeding was 0.998 (95% CI: 0.946–1.052) in patients treated with aspirin. Subgroup analysis showed that aspirin was more effective in patients with nonalcoholic cirrhosis than in those with other liver cirrhosis types. Second, 1,936 patients with ESRD with dialysis experienced a first IS during the follow-up. In a time-dependent analysis, HR for primary outcomes in patients treated with aspirin was 0.671 (p < 0.001) and that for clopidogrel was 0.933 (p = 0.497). With secondary outcomes, in patients treated with aspirin, HR for readmission for stroke was 0.715 (p = 0.002) and that for bleeding was 0.885 (p = 0.291). Finally, 287 aortic aneurysm cases were identified. HR for the primary outcome in patients with AAA/TAAA taking low-dose aspirin at each 90-day interval, based on the time-dependent analysis, was 1.000 (95% CI: 0.994–1.005) and that in patients with TAA was 1.010 (95% CI: 0.994–1.026), when compared with those with no exposure. In terms of secondary outcomes, HR for all-cause mortality was 0.995 (95% CI: 0.988–1.003) for patients with AAA/TAAA or 1.008 (95% CI: 0.991–1.026) for patients with TAA. Conclusion: Our finding suggests that antiplatelet therapy still offers a safe and effective treatment for the prevention of thrombotic diseases in special populations. Furthermore, additional research that would include other patient populations, such as those with intestinal failure, mild hepatic or renal failure, or other vascular diseases, is necessary to understand the effectiveness and safety of these drugs in the Taiwanese population.