評估合併使用Clopidogrel與其他藥理分類藥物於急性心肌梗塞病患之果效與藥物交互作用相關性研究

The Drug Interaction and Clinical Effectiveness Between Clopidogrel and other Pharmacological Drugs Following Acute Myocardial Infarction

陳崇鈺(Chung-Yu Chen)

指導教授 ： 黃耀斌

共同指導教授 ： 賴文德(Wen-Ter Lai)

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2010年)

https://doi.org/10.6832/KMU.2010.00144

摘要

研究背景: Clopidogrel在許多大型臨床試驗中發現部分病人服用Clopidogrel後，無法達到良好抑制血小板凝集的功效，則稱之為Clopidogrel抗阻性 (resistance)。目前對於Clopidogrel抗阻性被廣泛討論其判斷方式、成因、及結果影響。由於各研究所採用方式之不同，目前對於此類型之研究雖然數量很多，但並無完整的整理或指標可當作其參考。此外使用這些抗血小板藥物的病人經常合併有其他慢性疾病，在治療藥物複雜性的增加，也使抗血小板凝集功能有更多可能會受到其他藥物的影響。因此， Clopidogrel與其他藥物的合併產生之藥物交互作用，被認為可能是引起Clopidogrel抗阻性很重要的原因。
研究目的與目標: 使用整合分析探討Clopidogrel抗阻性與臨床追蹤指標之相關性並探討其代表指標。進一步使用其他文獻探討抗阻性病患可能合併使用其他合併藥物，而衍伸使用健保資料庫進行Clopidogrel與其他合併藥物於急性心肌梗塞變換之臨床治療果效與藥物交互作用之探討。
研究方法:本研究分為兩部分進行探討。第一部分採用文獻回顧及整合分析，探討各文獻之研究內容差異，依照各文獻所提供資料進行探討Clopidogrel抗阻性與臨床追蹤指標相關性之整合分析(嚴重不良心血管事件、心肌損傷程度、支架栓塞)；此外於整合分析，本研究也依各文獻中Clopidogrel 抗阻性病人相對於Clopidogrel反應正常者所使用其他合併藥物之分布與使用機會。第二部分採國衛院健保資料庫進行重疊病例對照研究，擷取2003年到2007年9月因急性心肌梗塞第一次住院過程中有使用Clopidogrel當作治療者，且於出院後持續使用者，利用個案之追蹤三個月，評估其追蹤期間是否又因急性心肌梗塞住院。於個案組及對照組追蹤期間合併本研究所探討之其他合併藥物之使用機會是否改變其再住院之風險，並依據不同時間加入進行探討。
研究結果: 本研究發現，經24篇文獻整合分析後發現無論採用發生人數比或經校正後勝算比去進行，具Clopidogrel抗阻性病人相對於反應正常者無論使用任何臨床追蹤指標皆有較高之機會再發生。但三種臨床追蹤指標於臨床評估使用上以嚴重不良心血管事件其勝算比較偏高，且在臨床使用上較方便；除受到Clopidogrel抗阻性影響外，其他研究次分類(投與劑量或觀察時間)仍可能影響到結果。而於國衛院全民健康保險資料庫分析後，於本研究中再住院者共68人及未再住院者575人，而於住院期間合併使用Clopidogrel與Amiodarone、Furosemide 顯著性增加研究個案90天內再住院之機會(Amiodarone AOR: 2.449,95% CI: 1.004-5.975; Furosemide AOR: 4.021,95% CI: 2.059-7.852)，但使用Isosorbide及Atorvastatin則會減少研究個案90天內再住院機會(Isosorbide AOR: 0.509,95% CI: 0.282-0.918; Atorvastatin AOR: 0.265,95% CI: 0.106-0.602)。於出院後90天內合併使用Clopidogrel與Perindopril、Furosemide、Fenofibrate或Omeprazole 有顯著性增加研究個案90天內再住院機會(Perindopril AOR: 2.684,95% CI: 1.103-6.531; Furosemide AOR: 2.126,95% CI: 1.078-4.194; Fenofibrate AOR: 3.271,95% CI: 1.160-9.222; Omeprazole AOR: 3.697,95% CI: 1.025-13.335)，但使用Atorvastatin仍呈現顯著性減少再住院之機會 (Atorvastatin AOR: 0.360,95% CI: 0.159-0.812)。
結論與建議:目前對於Clopidogrel抗阻性或反應不良之定義、臨床影響及成因仍未有明確之共識，但Clopidogrel抗阻性之治療果效於各研究皆指出其風險相對較高。而經由本研究對於急性心肌梗塞病患且使用Clopidogrel之合併使用其他合併藥物其效益及可能藥物交互作用提供預測影響因子(predictor)，因此希望能提供給台灣本土臨床上治療急性心肌梗塞或使用Clopidogrel之患者能有其依據。但仍建議使用這些可能影響因子進行於臨床上血小板凝集變化之探討，及對於台灣本土使用Clopidogrel後呈現抗阻性之病患進行流行病學研究，以建立台灣本土病患使用Clopidogrel之指引。

關鍵字

Clopidogrel抗阻性 ； 藥物交互作用 ； 整合分析 ； 健保資料庫 ； 急性心肌梗塞

並列摘要

Background: Clopidogrel has been used in the antiplatelet therapy for patients with cardiovascular disease, especially after coronary artery disease. Recent researches have suggested that medications inhibit the prodrug of Clopidogrel to its active form, in particular CYP 2C19 or CYP 3A4, influence the antiplatelet effectiveness with an increased risk of cardiovascular events. Cardiovascular disease drugs are often combined with Clopidogrel , but the clinical significance of these drug interactions are still unknown
Aims: Using meta-analysis to evaluate the correlation between Clopidogrel resistance and clinical outcome, and use the suitable surrogate to find the possible predictor of Clopidogrel resistance. Next, using the Longitudinal Health Insurance Database 2005 to investigate would concomitant use of Clopidogrel and other drugs in acute myocardial infarction patients change odds ratio of readmission for acute myocardial infarction .
Methods: An electronic literature search through different database of retrieved articles up to March, 2010 was conducted. Studies were included if they had prospective design, definition of Clopidogrel resistance and measurement, and the following outcome and adequate statistical analysis. In other part, we also conducted a population-based nested case-control study among patients who were admitted for AMI, and then discharged between April 1, 2003 to September 31, 2007 , who also started using Clopidogrel following hospital and discharge after AMI. In our study, cases were readmitted for AMI within 90 days after discharge, and the others were divided into contorls. And we also categorized exposure to cardiovascular disease drugs into three periods: before 90 days to hospital, hospitalization, after discharge to 90 days. Multivariable conditional logistic regressions were used to estimate the association between cases and controls in three periods.
Results: Firstly, twenty-four studies were included, totaling 8057 CAD patients followed for a time ranging from one months to two years.The cumulative analysis reported Clopidogrel resistance was significantly associated with an increased risk of different clinical outcomes(OR =5.23, 95% CI: 3.29-8.34; p<0.0001). And major adverse cardiac events had a high trend OR to compare with other clinical outcomes. However, from subgroup analysis, there were a greater risk of CVD recurrences for patients treated with 300 mg loading dose, with a lesser period of treatment, and different laboratory method. Secondly, we identified 68 cases readmitted with AMI and 575 controls. After extensive multivariable adjustment, concomitant using of Clopidogrel and Amiodarone, or Furosemide at hospital were associated with an increased risk of reinfarction (Amiodarone: Adjusted odd ratio: 2.449, 95% CI: 1.004-5.975; Furosemide AOR: 4.021, 95% CI: 2.059-7.852). In the other, if patients discharge and continuously combine using Clopidogrel with Furosemide , Perindopril, Fenofibrate or Omeprazole were associated with an increased risk of readmitted for AMI (Perindopril AOR: 2.684, 95% CI: 1.103-6.531; Furosemide AOR: 2.126, 95% CI: 1.078-4.194; Fenofibrate AOR: 3.271, 95% CI: 1.160-9.222; Omeprazole AOR: 3.697, 95% CI: 1.025-13.335). We also found that concomitant using of Clopidogrel and Atorvastatin at hospital or discharge were associated with an decreased risk of reinfarction (at hospital: AOR: 0.265, 95% CI: 0.106-0.602; discharge AOR: 0.360, 95% CI: 0.159-0.812).
Conclusions: The meta-analysis indicated a significant association between Clopidogrel resistance and recurrent cardiovascular events. Patients used Clopidogrel following AMI, concomitant using with specific cardiovascular disease drugs (Amiodarone, Furosemide, Perindopril, Fenofibrate) were associated with increased risks of recurrent AMI within 90 days.From these predictors of Clopidogrel resistance, there still need some in vitro clinical stuies to understand the drug drug interaction and clinical effectivness between Clopidogrel and other drugs.

並列關鍵字

Clopidogrel resistance ； National health insurance database ； Meta-analysis ； Acute myocardial infarction

參考文獻

參考文獻

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