心肌梗塞經皮冠狀動脈介入治療後服用雙重抗血小板藥物與合併使用其他藥物風險分析

The association between use of dual antiplatelet agent with and without concurrent medication and the risk in the patient who had coronary artery disease after percutaneous coronary intervention

戴笠修(Li-Hsiu Tai)

指導教授 ： 葉兆斌 ； 周明智

中山醫學大學/醫學院/醫學研究所/碩士(2021年)

https://doi.org/10.6834/csmu202100119

摘要

研究目的：對於心肌梗塞的病患，經皮冠狀動脈介入治療（Percutaneous coronary intervention，PCI），是臨床上常用來治療的方式，方法包含氣球擴張術（PTCA）與血管支架置放等，術後加上雙重抗血小板藥物（Dual antiplatelet therapy，DAPT）為急性冠心症及PCI術後標準治療，藥物包含Aspirin加上一種P2Y12 抑制劑，如Clopidogrel或Ticagrelor等，但此類病患常合併使用許多藥物，而這些藥物中，不論是藥物機轉或者動物實驗裡，多少有藥物交互作用的風險，可能會造成DAPT的效果不佳或者增加出血等病發症的風險。在本文中，我們使用台灣國家健康保險研究資料庫（NHIRD）的數據來進行回溯性世代研究，調查心肌梗塞經皮冠狀動脈介入治療後病患使用雙重抗血小板藥物合併其他藥物的風險分析。
研究方法及資料：本研究我們使用回溯性世代研究分析，總共收集1008位第一次心肌梗塞接受PCI並且服用DAPT的病患。根據國際疾病分類，使用第九版臨床診斷代碼（ICD-9）。本研究收錄西元2006年到2012年中，第一次心肌梗塞冠狀動脈支架置放術後的病患，排除冠狀動脈攝影後，兩個月內有施行冠狀動脈繞道手術（Coronary artery bypass graft，CABG），計畫性PCI（心肌梗塞後兩次PCI間隔小於兩個月），術後無服用DAPT的病患後。觀察接受PCI後，服用DAPT並合併使用其他藥物下的死亡率、再阻塞率、重大出血發生率。
研究結果：在此研究中，我們追蹤心肌梗塞病患接受PCI後服用DAPT合併使用其他藥物一年及長期使用的死亡率、再阻塞率、重大出血發生率。一年追蹤期中合併使用Diuretics、Laxatives、Proton-pump inhibitor（PPIs）會增加死亡率；ARBs（Angiotensin II receptor blockers）、BZD（Benzodiazepine）與再阻塞率相關；Diuretics、PPIs會增加出血機率。長期追蹤下，合併Diuretics、Laxatives、Heparin、NSAIDs與較高的死亡率相關；ARBs與BZD與較高再阻塞率相關；合併使用PPIs與較高的出血事件相關。在本研究中，不論是一年或是整個追蹤期間，Statin皆與較低的死亡率相關。
結論與建議：本研究發現心肌梗塞病患接受冠狀動脈支架置入後使用DAPT的病患，一年追蹤期中合併使用Diuretics、Laxatives、PPIs與死亡率增加相關；ARBs、BZD與再阻塞率相關；Diuretics、PPIs與較高的出血機率相關。長期追蹤下，合併Diuretics、Laxatives、Heparin、NSAIDs與較高的死亡率相關。ARBs與BZD與較高再阻塞率相關。合併使用PPIs與較高的出血事件相關。臨床醫師使用時，須注意相關風險。

關鍵字

雙重抗血小板藥物 ； 藥物交互作用 ； 世代研究 ； 藥物交互作用 ； 世代研究

並列摘要

Objective:
Dual antiplatelet therapy (DAPT) is a standard therapy for patients with myocardial infarction (MI), the agents included Aspirin and P2Y12 inhibitor, such as Clopidogrel, Ticagrelor, Prasugrel. However, many drugs have drug-drug interaction (DDI) with these drugs. It has been a concern that would DDI affects the clinical outcome of ACS. Therefore, we conducted a population-based cohort study to investigate the outcome of DAPT with or without concurrent drugs which had DDI with either Aspirin or Clopidogrel by using the data from National Health Insurance Research Database (NHIRD) of Taiwan.
Methods and Materials:
Retrospective cohort study using data from NHIRD and including 1008 patients with first time MI who received either bare-metal stents (BMS) or drug-eluting stents (DES) implantation and DAPT (Aspirin and Clopidogrel) from January 1, 2006, through December 31, 2012 , with final follow-up on December 31, 2016. Patients was included by diagnostic code according to International Classification of Diseases, Ninth Edition, Clinical Modification (ICD 9 CM). All patients were aged ≧ 18 years. Exposures drugs was included according to Anatomical Therapeutic Chemical Classification (ATC) code. Main outcomes were all-cased mortality, in-stent restenosis, major bleeding. Adjusted incidence rate of DAPT with or without concurrent medications were estimated using Poisson regression.
Results:
Among 1008 patients with first time MI; BMS implantation, 605 patients; DES implantation, 403 patients. After one year follow-up, concurrent use of diuretics (aHR: 2.11, 95% CI 1.17 - 3.83), laxatives (aHR: 3.57, 95% CI 1.86 - 6.85) and PPIs (aHR: 3.24, 95% CI 1.82- 5.77) had an increase in adjusted incidence rates of mortality; concurrent use of ARBs (aHR: 1.62, 95% CI 1.19 - 2.19), BZD (aHR: 1.80, 95% CI 1.33 - 2.43) had an increase in adjusted incidence rates of in-stent restenosis; concurrent use of diuretics (aHR: 2.64, 95% CI 1.46- 4.80), PPIs (aHR: 4.41, 95% CI 2.15 - 9.04), DPP-4 inhibitor (aHR: 3.10, 95% CI 1.32 - 7.24) had an increase in adjusted incidence rates of major bleeding. Statins was associated with lower mortality (aHR: 0.31, 95% CI 0.18 - 0.53). In whole study period, concurrent use of diuretics (aHR: 1.99, 95% CI 1.36 - 2.90), laxatives (aHR: 1.97, 95% CI 1.34 - 2.89), Heparin (aHR: 1.81, 95% CI 1.18 - 2.75) and NSAIDs (aHR: 1.72, 95% CI 1.11 - 2.64) had an increase in adjusted incidence rates of mortality. ARBs (aHR: 1.39, 95% CI 1.10 - 1.74), BZD (aHR: 1.32, 95% CI 1.05 - 1.67) had an increase in adjusted incidence rates of in-stent restenosis. PPIs was associated with higher major bleeding rate (aHR: 2.81, 95% CI 1.72 - 4.60). Combine usage with Statin had a significant lower in mortality (aHR: 0.54, 95% CI 0.38 - 0.75).
Conclusion and Suggestion:
Among patients taking DAPT for MI, concurrent use of diuretics, laxatives, PPIs was associated with increased risk of mortality. Concurrent use of ARBs, BZD was associated with increased risks of in-stent restenosis and diuretics, PPIs, DPP-4 inhibitor was associated with higher risk of major bleeding. Statins can lower the mortality either short-term or long-term. Physician prescribing DAPT should consider the potential risks associated with concomitant use of other drugs

並列關鍵字

Dual antiplatelet therapy ； Drug interaction ； population-based cohort study

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