急性冠心症病人使用雙重抗血小板藥物併用鈣離子阻斷劑與再發生心血管事件之分析

Concomitant use of Calcium Channel Blockers with Dual Antiplatelet Therapy and Recurrent Cardiovascular Events for Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention

王貞予(Chen-Yu Wang)

指導教授 ： 蕭斐元

共同指導教授 ： 林珍芳

國立臺灣大學/醫學院/臨床藥學研究所/碩士(2014年)

https://doi.org/10.6342/NTU.2014.10648

摘要

研究背景:
相關研究顯示併用calcium channel blockers (CCBs)會降低clopidogrel抑制血小板活性的效果，然而連結臨床結果之研究不足且能提供的資訊相當有限。
研究目的:
分析併用CCBs和clopidogrel是否會影響clopidogrel的臨床效益。為使研究結果更能符合臨床需求，本研究進一步探討在不同CCBs持有率(MPR:Medication possession ratio)、不同CCBs之種類和成分的情況下，對於clopidogrel臨床效益之影響是否存在差異。
研究方法:
本研究為一回溯性世代研究，利用2005-2011年台灣健保資料庫為資料來源，收集因第一次急性冠心症(ACS: acute coronary syndrome)住院並接受經皮冠狀動脈介入術(PCI: percutaneous coronary intervention)之病人，同時符合出院後一年內有使用dual antiplatelet therapy的族群。進一步依照出院後使用美國心臟醫學會及心臟協會治療指引建議之ACS二次預防藥物(包含:β-blockers、(ACEI/ARB: Angiotensin-converting enzyme inhibitor /Angiotensin receptor blocker)、statins)之情形，將病人分成三組。其中完全符合guideline組為使用三種預防藥物之病人，部分符合guideline組為使用一至二種預防藥物之病人，不符合guideline組為完全沒有使用二次預防藥物之病人。同時為了縮小自我選擇偏差，本研究利用傾向分數(propensity score)配對的方式，將使用CCBs的病人1:1配對找出沒有使用CCB的對照組。以Cox proportional hazard model 來分析追蹤期間CCBs的使用，對於clopidogrel預防ACS再住院效果之影響。本研究進一步將CCBs依MPR高低分組，以探討藥品使用量與研究終點之關係。另外，依CCBs之化學結構將其分成Dihydropyridine CCBs和Non-Dihydropyridine CCBs;以及對Pgp(P-glycoprotein)的抑制情形分成以Pgp-inhibiting CCBs和Non-Pgp-inhibiting CCBs分別探討不同種類CCBs之差異。最後，探討國內六種常用成分之CCBs的各別結果。
研究結果:
本研究共收納51925位病人，經過傾向分數配對後，完全符合guideline組使用CCB者與對照組人數比例為5374:5374 ; 部分符合組11164:11164；不符合組923:923。在校正過性別、年齡、共併症和併用藥物的影響過後，使用CCB的族群發生ACS再入院之風險較未使用CCB的族群低，此現象在各組均有相同結果。(完全符合組: HR=0.62 ( 95%CI =0.57-0.68, p<0.001); 部分符合組: HR=0.72 (0.68-0.76, p<0.001)；不符合組: HR=0.79 (0.66-0.94, p=0.0073))。
另外，CCBs的藥物持有率增加時，發生ACS再住院之風險也隨之上升，此現象在各組都有相同趨勢(於完全符合組: 0=1, HR=0.76 (0.67-0.81, p<0.001))。進一步分析不同種類之CCBs的結果時，發現Dihydropyridine類CCBs相較於Non-Dihydropyridine類CCBs，有較低之ACS再住院風險(完全符合組: HR=0.71 (0.60-0.84, p<0.001); 部分符合組: HR=0.77 (0.70-0.85, p<0.001)；不符合組: HR=0.82 (0.57-1.04, p=0.166))。而Pgp-inhibiting CCBs 相較於Non-Pgp- inhibiting CCBs 有較高的ACS再住院風險(完全符合組: HR= 1.23 ( 95%CI =1.07-1.41, p=0.003); 部分符合組: HR=1.14 ( 1.05-1.24, p=0.002)；不符合組: HR=1.37 (1.02-1.83, p=0.034)); 最後，分析單一成分時，發現國內最常用之六種CCBs成分(amlodipine、felodipine、nifedipine、 verapamil、diltiazem、lercanidipine)， 只有amlodipine的使用，在各組都能顯著降低ACS再住院之風險。反之，felodipine 在不符合guideline組的使用，相較於沒有使用CCB的對照組則會顯著上升ACS再住院之風險。
研究結論:
在使用二次預防藥物的情形下併用CCBs和clopidogrel不會下降ACS病人進行PCI之後使用clopidogrel的臨床效益。而CCBs和clopidogrel潛在交互作用方面，可能和CCBs的持有率存在一個dose-dependent的關係。在沒有使用任何ACS二次預防藥物的情形下，併用felodipine這個成分，則會顯著下降clopidogrel的臨床效益。此外，ACS之後病人存在多樣性，因此做相關藥物分析時建議分開探討且CCBs之各成分也有其不同臨床特性，不可視為單一種類等同視之

關鍵字

clopidogrel藥物交互作用 ； 鈣離子阻斷劑 ； 急性冠心症 ； 經皮冠狀動脈介入術 ； 再住院

並列摘要

Background: Existing studies have reported that calcium channel blockers (CCBs) may reduce pharmacological activity of clopidogrel and result in subsequent negative outcomes. However, studies assessing clinical outcomes in patients receiving both drugs are very limited.

Objectives: The objective of this population-based cohort study was therefore to investigate risks of recurrent hospitalization for acute coronary syndrome (ACS) in patients receiving percutaneous coronary intervention (PCI) who require ongoing dual antiplatelet therapy (aspirin + clopidogrel) with or without CCBs. Furthermore, we assess the outcome of medication possession ratio (MPR) of CCBs, different category of CCBs and individual component.

Methods: Using 2005-2011 Taiwan's National Health Insurance Research Database, we identified 51925 patients who first admitted for ACS, received PCI and used dual antiplatelet therapy within one year after they discharged. We further divided our study population into three subgroups based on the medication categories they used for secondary prevention for ACS, including β-blockers, ACEI (angiotensin-converting enzyme inhibitor)/ARB (angiotensin receptor blocker) and statins. Completely, partially and non- adherent groups consisted of patients using three categories, one or two categories and none of medications for secondary prevention, respectively. In order to minimize the variation between individual characteristics, we conduct 1:1 propensity score matching. Cox proportional hazard model were conducted to assess re-hospitalization for ACS in patients receiving clopidogrel therapy with or without CCBs. Forthermore, we use the MPR to assess the relationship between the amount of CCBs use and ACS re-hospitalization. We separate CCBs by their chemical structure as Dihydropyridine CCBs and Non-Dihydropyrydyne; and by their P-glycoprotein(Pgp) inhibiting property as Pgp-inhibiting CCBs and Non-Pgp-inhibiting CCBs, in order to assess the different of this two category CCBs. Finally, we assess the outcomes of the six most frequently use CCBs in Taiwan.
Results: Among clopidogrel users, concomitant use of CCBs was associated with a reduced hazard of re-hospitalization for ACS after adjusting for age, gender, co-morbidities, and co-medications (completely-adherent group: HR=0.62 (95% CI 0.57-0.68, p<0.001);partially-adherent group: HR=0.72 (0.68-0.76, p<0.001)；none-adherent group: HR=0.79 (0.66-0.94, p=0.0073)). When the MPR increased, the risk of re-hospitalization for ACS increased in all subgroups. (completely-adherent group: 0=1, HR=0.76 (0.67-0.81, p<0.001))。 In comparison with Dihydropyridine CCBs, Non-Dihydropyridine CCBs were associated with a higher hazard of re-hospitalization for ACS. (completely-adherent group: HR=1.41 (1.19-1.68, p<0.001); partially-adherent group: HR=1.30 (1.18-1.44, p<0.001)；none-adherent group: HR=1,22 (0.92-1.61, p=0.166)) And, amlodipine was associated with lower risk of ACS rehospitalization in all three subgroups, while felodipine was associated with higher risk of ACS rehospitalization in group of none apply to guideline.

Conclusion: This population-based cohort study found that concomitant use of clopidogrel and CCBs in patients who received PCI after ACS was not associated with an increasing risk of recurrent hospitalization. However, CCBs medication possession ratio and concomitance use of clopidogrel and felodipine in patients without secondary prevention medications may affect the risk of ACS rehospitalization.

並列關鍵字

clopidogrel drug interaction ； calcium cahnnel blockers ； acute coronary syndrome ； percutaneous coronary interventio ； rehospitalization

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