需使用雙重抗血小板製劑之心房顫動病人的抗血栓藥品臨床療效與安全性

Abstract

研究背景：心房顫動(atrial fibrillation; AF)病人若同時患有急性冠心症(acute coronary syndrome; ACS)或裝有冠狀動脈血管支架，需使用雙重抗血小板藥物(dual antiplatelet therapy; DAPT)和抗凝血劑(anticoagulant)以同時降低嚴重心血管不良事件(major adverse cardiovascular event; MACE)、支架栓塞(stent thrombosis)與中風發生的機會，但同時併用三種抗血栓藥品卻會增加出血風險。過去文獻針對不同抗血栓藥品組合間的療效與安全性則未有定論，且於亞洲進行的全人口研究有限。 研究目的：探討具備雙重抗血小板藥物適應症的心房顫動病人臨床上抗血栓藥品的處方型態及影響開立抗凝血劑的因子，並比較不同藥品組合發生心血管不良事件與嚴重出血的風險。 研究方法：本研究利用衛生福利部資料科學中心之全民健康保險資料庫進行回溯性世代研究(retrospective cohort study)，收錄2007至2016年因ACS或放置冠狀動脈血管支架入院的非瓣膜性心房顫動(non-valvular AF)病人。指標事件發生前一年內曾進行經皮動脈介入術(percutaneous coronoary intervention; PCI)、冠狀動脈繞道手術(coronary artery bypass graft surgery; CABG)或因ACS入院者則會被排除。病人群自出院後起開始追蹤一年，直到死亡、發生MACE或嚴重出血。追蹤期間使用的抗血栓藥品分為五個組合：單用抗血小板製劑(single antiplatelet therapy; SAPT)、單用抗凝血劑(single oral anticoagulant; SOAC)、DAPT、抗血小板製劑+抗凝血劑(稱為double therapy)與DAPT+抗凝血劑(稱為triple therapy)，並將這些藥品組合視為時間相依共變數(time-dependent covariate)，允許病人在追蹤期間內更換藥品組合。本研究使用多變項Cox回歸分析(multivariable Cox regression)比較不同藥品組合發生MACE(由因心血管疾病死亡、心肌梗塞[myocardial infarction; MI]與阻塞性中風/短暫性腦缺血發作[ischemic stroke/transient ischemic attack]組成)、死亡與嚴重出血的風險差異。此外，本研究亦進行敏感度分析與landmark analysis。 研究結果： 本研究收錄12905位病人，平均年齡71.7歲、男性占68.1%，CHA2DS2-VASc score中位數為3分(IQR: 2-4)。主診斷為ACS者占43.5%，另有82.6%裝有支架。出院時最常被開立的處方為DAPT(占61.4%)，其次為SAPT(占23.1%)，其餘則開立含抗凝血劑的組合，包含：SOAC (3.5%)、double therapy (5.7%)與triple therapy (6.2%)。裝有支架、主診斷為ACS、曾使用過aspirin與具嚴重出血病史均會顯著降低開立抗凝血劑的機會；而曾發生過中風、在2012-2017年納入分析與過去使用過抗凝血劑者，則有較高的機率使用抗凝血劑。 和DAPT相比，SAPT (adjusted hazard ratio (aHR) 1.12 [95% CI 0.98-1.29])、SOAC (aHR 0.96 [0.72-1.28])、double therapy (aHR 0.93 [0.74-1.17])與triple therapy (aHR 0.92 [0.66-1.28])發生MACE的風險沒有達到統計上顯著差異。和double therapy相比，triple therapy發生MACE的風險亦類似(aHR 0.99 [0.68-1.45])，但在出院後的90天內有降低MI發生的趨勢(aHR 0.46 [0.17-1.29])。嚴重出血方面，double therapy和DAPT的風險類似(aHR 1.04 [0.72-1.49])，而triple therapy無論和DAPT或double therapy相比，出血風險都顯著較高，aHR分別為1.85 [1.23-2.78]與1.78 [1.07-2.94]。 結論：AF合併ACS或裝有冠狀動脈血管支架的病人最常開立的藥品是DAPT。DAPT、double therapy與triple therapy發生心血管事件的風險類似，但triple therapy於出院後90天內發生心肌梗塞的風險略低於double therapy。嚴重出血方面，DAPT與double therapy的風險無顯著差異，但triple therapy和兩者相比均會增加近一倍的風險。

Background: For atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI) with stent or having concomitant acute coronary syndrome (ACS), dual antiplatelet (DAPT) and anticoagulant are warranted to prevent major adverse cardiovascular event (MACE), stent thrombosis and stroke. However, using three antithrombotic agents might increase bleeding risk. Previous studies showed inconsistent results regarding the effectiveness and safety of different antithrombotic regimens. In addition, only a few of them were population-level studies conducted in Asia. Objectives: This study aimed to compare risks of MACE and major bleeding across different antithrombotic regimens in AF patients with indications of DAPT. Prescription patterns and factors influencing anticoagulant prescription were also explored. Methods: We conducted a retrospective cohort study by using Taiwan’s National Health Insurance Research Database. Non-valvular AF patients who newly underwent PCI with stents or hospitalized due to ACS in 2007 to 2016 were included. Patients who received PCI, coronary artery bypass graft or hospitalized for ACS one year before inclusion were excluded. The cohort was followed until death, MACE, bleeding events occurred or one year after discharge. All prescriptions of antithrombotic therapy received by the study cohort were captured daily and categorized into five regimens: single antiplatelet (SAPT), single oral anticoagulant (SOAC), dual antiplatelet (DAPT), SAPT+SOAC (double therapy) and DAPT+SOAC (triple therapy). These prescriptions were measured as time-dependent covariates to allow regimen switches during follow-up. We used multivariable Cox regression to compare 3-point MACE (myocardial infarction, ischemic stroke/transient ischemic attack and death from cardiovascular causes), all-cause mortality and major bleeding risk of aforementioned antithrombotic regimens. We also performed sensitivity analyses and landmark analyses. Results: We identified 12,905 patients (mean age 71.7; male 68.1%; median CHA2DS2-VASc score 3 [IQR 2-4]). Among them, 43.5% were admitted due to ACS and 82.6% had stent insertions. Most of them (61.4%) received DAPT at discharge, followed by SAPT (23.1%), triple therapy (6.2%), double therapy (5.7%) and SOAC (3.5%). Multivariable logistic regression showed stent insertions, ACS as principal diagnosis, aspirin history and major bleeding history significantly reduced the odds of being prescribed anticoagulant. On the other hand, patients who had ischemic stroke before, discharged from hospital in 2012-2017 or received oral anticoagulant before index event were more likely to receive anticoagulants. As compared with DAPT, there was no significant difference in 3-point MACE among other four antithrombotic regimens (SAPT: adjusted HR (aHR) 1.12 [95% CI 0.98-1.29]; SOAC: aHR 0.96 [0.72-1.28]; double: aHR 0.93 [0.74-1.17]; triple: aHR 0.92 [0.66-1.28]). We also found similar risk of MACE between double therapy and triple therapy (aHR 0.99 [0.68-1.45]). However, triple therapy had a trend toward less risk of MI as compared with double therapy in the first 90 days after discharge (aHR 0.46 [0.17-1.29]). DAPT and double therapy were comparable in major bleeding risk (aHR 1.04 [0.72-1.49]). By contrast, triple therapy was associated with a nearly two-fold risk of major bleeding comparing to both DAPT and double therapy (aHR 1.85 [1.23-2.78] and aHR 1.78 [1.07-2.94], respectively). Conclusion: Most of the AF patients undergoing PCI with stents or having concomitant ACS received DAPT at discharge. There were comparable risks of MACE among the five antithrombotic regimens (SAPT, SOAC, DAPT, double therapy and triple therapy) identified, but triple therapy had a slightly lower risk of MI comparing to double therapy, especially in the first 90 days after discharge. Nevertheless, triple therapy resulted in a nearly two-fold risk of major bleeding when comparing to DAPT as well as double therapy.