急性冠心症病人使用雙重抗血小板藥物療程時間與再發生心血管事件之風險分析

研究背景: 臨床試驗已證實雙重抗血小板藥物(aspirin併用clopidogrel)預防急性冠心症病人再發生心血管事件的效用，目前美國心臟學會治療指引建議急性冠心症病人應併用aspirin與clopidogrel至少12個月，反觀我國健保目前僅給付clopidogrel併用aspirin最長達9個月，可知兩者之間並不一致。此外，近年來許多文獻顯示塗藥支架可能增加晚期支架栓塞的風險，而病人若提前停用雙重抗血小板藥物亦會顯著增加支架栓塞發生率，故對於塗藥支架病人而言，最適當的雙重抗血小板藥物療程應維持多久，目前仍不甚確定，而有限的資料尚未能證實療程超過一年是否具有臨床效益。研究目的: (1)比較台灣健保給付 (九個月) 與國際學會治療指引建議的併用一年，療程長短對於病人預後再發生心血管事件的影響。(2)探討植入塗藥支架病人延長併用clopidogrel及aspirin超過一年的必要性。研究方法: 本研究為一回溯性世代研究，以北部某醫學中心醫令系統資料庫及紙本病歷為研究材料，篩選出2007年7月至2009年6月新住院診斷為急性冠心症(ACS)且接受經皮冠狀動脈介入術之clopidogrel使用病人，第一部分為處方型態分析:分析研究族群clopidogrel與aspirin的開方情形及療程時間。第二部分為描述性分析及存活分析:將同一群研究族群依三個時間點進行分析，而這三個時間點分別是病人首次ACS出院後的九個月、十二個月及十五個月，研究終點定義為「再次ACS住院事件」。研究分為三部分—將研究族群依九個月內、十二個月內及十五個月內使用clopidogrel情形分別分為「提前停藥組」及「持續用藥組」，首先分析兩組間背景資料的差異，其次利用time-dependent Cox’s proportional hazard model進行存活分析，探討clopidogrel療程對於研究終點的影響，並篩選植入塗藥支架病人進行次群體分析。研究結果: 研究族群共975人，平均追蹤時間為27個月。 (一)處方型態分析結果:研究族群一年內使用clopidogrel平均天數為259.38±114.13天，而療程超過9個月的病人占57.4 %，此群病人使用之中位數天數為364天，有48.6 %病人曾自費使用。 (二)描述性分析:影響病人使用≥12個月clopidogrel療程的因素包含—病人初次入院為心肌梗塞表現、多條血管阻塞、植入的支架為塗藥支架、支架放置在RCA、支架總長度較長、支架徑寬較小或病人患有高血壓；而影響病人使用≥15個月clopidogrel療程的因素，則包含—病人年紀較大、屬於多條血管阻塞、阻塞位置位於ostium、植入的支架為塗藥支架、支架放置在left main coronary artery (LM)、植入兩支以上的支架或支架總長度較長。 (三)存活分析結果: a)九個月療程分析，首次ACS出院(index date)九個月後仍存在研究中的有744位病人，將其依clopidogrel用藥情形分為「9個月前提前停藥組」292人及「9個月持續用藥組」452人，校正可能的干擾因子後，「9個月持續用藥組」的adjusted hazard ratio (HR)為0.69 (95 % CI=0.48-1.00, p=0.05)，顯示clopidogrel療程維持至少9個月能降低病人再次ACS住院的風險。 b)十二個月療程分析，index date後12個月仍存在研究中的病人有699人，「12個月前提前停藥組」有382人，「12個月持續用藥組」有317人，「12個月持續用藥組」的adjusted hazard ratio (HR)為0.59 (95 % CI=0.36-0.95, p=0.03)，由此可知維持療程至少12個月能顯著降低病人再次ACS住院風險。 c)十五個月療程分析，index date後15個月仍存在研究中共653人，「15個月前提前停藥組」有489人，「15個月持續用藥組」則有164人，存活分析結果顯示「15個月持續用藥組」的adjusted HR為0.57 (95 % CI=0.29-1.13，p=0.11)，並未發現使用clopidogrel大於等於15個月有顯著之效益。 d)塗藥支架次群體分析，「使用clopidogrel大於等於9個月」並未得到顯著意義，adjusted hazard ratio為0.68 (95 % CI=0.44-1.06，p=0.09)，但「使用clopidogrel大於等於12個月」則達到統計上的顯著，adjusted hazard ratio為0.52 (95% CI=0.29-0.92，p=0.02)，顯示植入塗藥支架病人若僅服用clopidogrel至9個月並未能顯著降低再次ACS住院事件風險，必須要服用至少12個月才有顯著效益。而「使用clopidogrel大於等於15個月」則並未看到顯著效益，adjusted HR為0.76 (95 % CI=0.37-1.56，p=0.45)。結論: 急性冠心症病人應於術後維持至少12個月的clopidogrel療程，尤其對於塗藥支架的病人而言，完成12個月療程的重要性更為顯著。相較之下，健保給付的9個月療程稍顯不足，故在此建議健保放寬給付clopidogrel併用aspirin達12個月。

關鍵字

clopidogrel ；急性冠心症；雙重抗血小板藥物； clopidogrel療程；塗藥支架

並列摘要

Background: Results from randomized studies have confirmed the efficacy of dual antiplatelet therapy of aspirin and clopidogrel in the reduction of the incidence of recurrent cardiovascular events. Current ACC/AHA guidelines recommend that in addition to aspirin, clopidogrel should be continued for 12 months in patients with acute coronary syndrome (ACS). However, the reimbursement program of NHI only pays for the cost on clopidogrel in addition to aspirin up to 9 months, 3 months shorter than that suggested by the ACC/AHA guideline. Moreover, there have been numerous reports of late stent thrombosis in drug-eluting stent-treated patients, particularly after premature discontinuation of dual antiplatelet therapy. The optimal duration of dual antiplatelet therapy for patients receiving drug-eluting stents (DES) is not entirely clear so far. The benefit of extended therapy beyond 1 year is still uncertain. Objectives: (1) To investigate the effect of dual antiplatelet therapy duration on the long-term clinical outcomes of ACS patients. (2) To evaluate the necessity of the use of dual antiplatelet therapy for more than 12 months in DES-treated patients. Methods: A retrospective cohort study was conducted using the computerized medical system and patient records in a medical center. We identified new ACS hospitalization patients receiving percutaneous coronary intervention and using clopidogrel after discharge during 2007/7 to 2009/6. Prescription analysis. We analysed the prescriptions patterns and mean duration of clopidogrel and aspirin use in the study population. Descriptive analysis. According to the duration of clopidogrel use within certain timeframes (9 months, 12 months or 15 months) after hospital discharge, we categorized the study population into “Premature DC group” and “Continuous group”. Then we compared the demographic and clinical characteristics between the two groups. Survival analysis. Our study endpoint was ACS-related rehospitalization. We used time-dependent Cox’s proportional hazard model to evaluate the hazard ratio (HR) between clopidogrel continuers and discontinuers for ACS-related rehospitalization. Besides, we performed similar analyses in the subgroup of DES-treated patients. Results: A total of 975 patients were included in this study. The mean duration of follow-up was 27 months. Prescription analysis. The mean clopidogrel-covered days were 259.38 days with an interquartile range of 145.25 to 373.51 days. There were 57.4 % of patients received duration of clopidogrel beyond 9 months, the median number of clopidogrel-covered days was 364 days, and 48.6 % of them ever had self-pay clopidogrel. Descriptive analysis. Patients with ≧12 months duration of clopidogrel therapy were more likely to present with MI at the first ACS hospitalization, have hypertension, multivessel disease, DES implantation, lesions located at right coronary artery (RCA), longer stent length and smaller stent diameter. Patients with≧15 months duration were older and more likely to have multivessel disease, ostium lesion, DES implantation, lesion located at LM, ≧2 stents implantation and longer stent length. Survival analysis. The clopidogrel therapy ≧9 months reduced risk for ACS-rehospitalization (adjusted hazard ratio [HR]=0.69; 95 % CI=0.48-1.00; p=0.05). Those who received clopidogrel for ≧12 months also had a lower ACS-rehospitalization rate (adjusted HR=0.59; 95 % CI=0.36-0.95; p=0.03). However, clopidogrel therapy ≧15 months did not show a significant benefit (adjusted HR=0.57; 95 % CI=0.29-1.13; p=0.11). In DES subgroup analysis, those who received clopidogrel for ≧12 months also had a lower ACS-rehospitalization rate (adjusted HR=0.52; 95 % CI=0.29-0.92; p=0.02). However, therapy duration ≧9 months was not associated with lower incidence of ACS-rehospitalization (adjusted HR=0.68; 95 % CI=0.44-1.06; p=0.09). This meant that clopidogrel therapy up to 9 months was not sufficient to those with DES, and it showed the benefit only if duration of clopidogrel use up to 12 months. Besides, clopidogrel therapy≧15 months did not reduce risk for ACS-rehospitalization (adjusted HR=0.76; 95 % CI=0.37-1.56; p=0.45). Conclusion: 12 months of clopidogrel therapy may be ideal for all patients with acute coronary syndrome, especially if a DES is implanted. In contrast, clopidogrel therapy up to 9 months covered by NHI showed insufficiency to provide maximum benefit. Therefore, we suggest the reimbursement from NHI to provide the addition of clopidogrel to aspirin up to 12 months.

並列關鍵字

clopidogrel ； acute coronary syndrome ； dual antiplatelet therapy ； duration of clopidogrel ； drug-eluting stents

參考文獻

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4. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665-71.

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急性冠心症病人使用雙重抗血小板藥物療程時間與再發生心血管事件之風險分析

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