非手術型主動脈疾病病人使用內科藥物之效果評估

Evaluating the Effectiveness of Medical Therapy on Non-operated Aortic Diseases

王詩涵(Shih-Han Wang)

指導教授 ： 黃耀斌

高雄醫學大學/藥學院/藥學系臨床藥學碩士班/碩士(2014年)

https://doi.org/10.6832/KMU.2014.00121

摘要

研究背景：主動脈疾病可分為主動脈剝離與主動脈瘤，一旦破裂而導致體內大出血就會危及病人生命。目前研究已證實主動脈直徑大小和破裂機率有關，但尚未有藥物被證實可以延緩主動脈的擴張速率。近年來研究顯示，HMG-CoA還原酶抑制劑 (statin)、血管張力素轉換酶抑制劑 (angiotensin-converting enzyme inhibitor, ACEI)、血管張力素受體阻斷劑 (angiotensin II receptor blocker, ARB)、乙型受體阻斷劑 (??-blocker)和鈣離子通道阻斷劑 (calcium channel blocker , CCB)，除了本身的降血脂與降血壓效果，還能抑制主動脈擴張的病理機轉，另外，抗血小板藥物用於主動脈疾病的安全性仍有爭議。

研究目的與目標：本研究希望藉由系統性文獻回顧及整合分析，探討主動脈疾病經由內科藥物治療之成效，並利用醫院臨床病歷資料，以期評估臺灣地區B型主動脈剝離病人 (type B aortic dissection, TBAD)經由內科藥物治療之成效。

研究方法：本研究分為兩個部分。第一部分為系統性文獻回顧與整合分析，以探討內科藥物用於主動脈疾病之臨床效果，搜尋過程將持續至2014年6月，探討主動脈疾病使用statin, ACEI, ARB, ??-blocker, CCB和抗血小板藥物的文獻都會被納入，評估結果包含死亡、手術修復、主動脈相關事件與主動脈擴張速率。第二部分為病歷回溯研究，收錄臺灣南部某醫學中心從2008年1月到2013年6月新診斷為TBAD的病人，其首次診斷為納入研究日，評估臺灣TBAD病人基本資料、疾病資訊、藥物處方型態、事件發生情形，以及內科藥物與預後之關係。

研究結果與討論：系統性文獻回顧與整合分析研究共納入19篇世代研究，探討TBAD的文獻共3篇、胸主動脈瘤 (thoracic aortic aneurysm, TAA)共3篇，腹主動脈瘤 (abdominal aortic aneurysm, AAA)共14篇，結果顯示CCB可減少TBAD族群45%全死因死亡之風險 (odd ratio [OR]=0.55, 95% confidence interval [CI]: 0.35~0.88)；TAA之分析結果顯示statin可減少50%手術修復(OR=0.50, 95% CI: 0.38~0.67)與47%主動脈相關事件 (OR=0.53, 95% CI: 0.40~0.69)之風險，抗血小板藥物會增加69%發生主動脈相關事件之風險 (OR=1.69, 95% CI: 1.13~2.52)；AAA之分析結果顯示statin可降低主動脈擴張速率1.5 mm/year (mean difference=-1.50, 95% CI: -2.36~-0.64)，ARB可降低主動脈擴張速率0.91mm/year (mean difference=-0.91, 95% CI: -1.78~-0.03)。病歷回溯研究共納入106位非手術型TBAD個案，平均追蹤時間為2.75年，共病症以高血壓最多，其次為高血脂和糖尿病，研究終點多發生於納入日後6個月內，持續使用2種以上降血壓藥物的個案佔80%，不同降血壓藥物數目分組與ACEI/ARB使用與否對於事件發生並無顯著影響。另外，以累積日劑量達到28個單位定義為用藥組，發現抗血小板藥物會增加4.14倍發生手術修復或死亡之風險 (adjusted HR [aHR]= 4.14, 95% CI: 1.03~16.66)，與6.06倍發生全因性死亡之風險 (aHR= 6.06, 95% CI: 1.18~31.16)。

結論：系統性文獻回顧與整合分析結果發現statin和ARB對主動脈瘤病人有益，而抗血小板藥物會增加TAA族群之風險，但所有納入研究皆為觀察性研究，且近一半文獻品質不佳，因此未來還需要大型前瞻性世代研究或臨床試驗探討其效果。於病歷回溯發現抗血小板藥物有增加TBAD族群手術修復或死亡之風險，建議未來可針對藥物劑量作進一步探討。

關鍵字

主動脈瘤 ； 主動脈剝離 ； 系統性文獻回顧與整合分析 ； 病歷回溯 ； HMG-CoA還原酶抑制劑 ； 血管張力素轉換酶抑制劑 ； 血管張力素受體阻斷劑 ； 乙型受體阻斷劑 ； 鈣離子通道阻斷劑 ； 抗血小板藥物

並列摘要

Background: Aortic diseases can divide as aortic dissection and aortic aneurysm, and the mortality is high in elderly when the rupture occurs. Present studies have confirmed that the probability of aortic rupture is associated with aortic diameter. However, there is no medication proven to reduce the growth rate of aortic diameter. Recently, several studies suggest that some medication can prove beneficial of aortic diseases not because of their ability to reduce blood pressure and lipid profile, including statin, angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), ??-blocker, and calcium channel blocker (CCB). Besides, safety of antiplatelets for aortic diseases is still controversial.

Aim and objectives: In this study, we design a systematic review and meta-analysis to evaluate the effectiveness of statin, ACEI, ARB, ??-blocker, CCB and antiplatelets in aortic diseases population, and conduct a retrospective cohort study at a medical center in southern Taiwan to obtain local information of type B aortic dissection (TBAD), finally compare the results from each other.

Methods: The study is divided into two parts. The first part is a systematic review and meta-analysis to conduct the clinical effect of medication for aortic disease patients. The search process will continue until June 2014. Study endpoints include death, surgery repair, aortic events and expansion rate of aortic diameter. The second part is a retrospective cohort study. We plan to review the hospital records of TBAD population at a medical center in Southern Taiwan from January 2008 to June 2013, and assess baseline characristics, disease information, prescribing pattern, event rate, and clinical effect of medication. Index date defined as first TBAD diagnosis date.

Results and discussion: The systematic review and meta-analysis identified a total of 19 cohort studies, 3 studies for TBAD, 3 studies for thoracic aortic aneurysm (TAA), and 14 studies for abdominal aortic aneurysm (AAA). The results of TBAD showed that CCB significantly decrease all-cause mortality (odd ratio [OR]=0.55, 95% confidence interval [CI]: 0.35~0.88). The results of TAA showed that statin significantly decrease the events of surgery repair (OR=0.50, 95% CI: 0.38~0.67) and the events attributed to aortic diseases (OR=0.53, 95% CI: 0.40~0.69), and antiplatelets significantly increase the events attributed to aortic diseases (OR=1.69, 95% CI: 1.13~2.52). The results of AAA showed that statin (mean difference=-1.50, 95% CI -2.36~-0.64) and ARB (mean difference=-0.91, 95% CI: -1.78~-0.03) significantly decrease the expansion rate of aortic diameter. We included 106 patients in the hospital-based cohort study and the mean follow-up period was 2.75 years. The most common comorbidities were hypertension, followed by dyslipidemia and diabetic mellitus. Study endpoints mostly occurred within 6 months after index date. About 80% patients continued using two or more antihypertensive drugs, and no significant effect among different groups based on number of antihypertensive drugs and ACEI/ARB use or not. Besides, antiplatelet user, which defined as cumulative daily dose of antiplatelets more than 28 units, significantly increase the events of surgery repair or death (adjusted HR [aHR]= 4.14, 95% CI: 1.03~16.66) and all-cause mortality (aHR= 6.06, 95% CI: 1.18~31.16).

Conclusion: The systematic review and meta-analysis showed that statin and ARB beneficial for aortic aneurysm population, but antiplatelets increase the risk of TAA population. All the included studies were observational studies and nearly half were low quality, so further prospective studies might be required to determine the effect. The cohort study showed that antiplatelets increased the risk of surgery repair or death in TBAD population. Further study can investigate whether dose relationship or not of antiplatelets.

並列關鍵字

aortic aneurysm ； aortic dissection ； systematic review and meta-analysis ； chart review ； HMG-CoA reductase inhibitor ； angiotensin-converting enzyme inhibitor ； angiotensin II receptor blocker ； beta-blocker ； calcium channel blocker ； antiplatelets

參考文獻

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