冠心病患者替格瑞洛停药原因及停药对临床转归的影响分析

The reasons and impact of ticagrelor withdrawal in patients with coronary artery disease

目的分析冠心病患者替格瑞洛停药原因及停药对临床转归的影响。方法连续募集2014年1月至2015年7月在解放军总医院心内科住院并接受替格瑞洛抗血小板治疗的冠心病患者642例，分析患者3个月内替格瑞洛停用的发生情况及停药原因。对入选患者经皮冠状动脉介入术（PCI）后随访6个月，比较患者3个月内停用替格瑞洛与持续服用该药发生缺血事件[包括主要缺血事件（心源性死亡、非致死性心肌梗死、缺血性脑卒中、明确或可能的支架内血栓、冠状动脉血管重建）和次要缺血事件（因不稳定型心绞痛再人院）]及出血终点事件[包括心肌梗死溶栓治疗试验（TIMI）主要和次要出血]的差异。结果本研究中164例（25．55％）患者分别在住院期间（42例，25．61％）、出院当天（7例，4．27％）和出院至随访3个月时（115例，70．12％）停用替格瑞洛。停药患者在不同冠心病诊断中的分布为不稳定型心绞痛占78．05％、ST段抬高型心肌梗死（STEMI）占13．41％、非ST段抬高型心肌梗死（non．STEMI）占4．27％和稳定型冠心病占4．27％。院内或出院时替格瑞洛停用的原因主要为替格瑞洛相关呼吸困难（32．65％）、出血（22．45％）和非复杂病变的PCI术（18．37％）；院外停用替格瑞洛的原因主要为当地无法购买替格瑞洛（68．70％）和经济原因（16．52％）。停药后，除10例死亡患者，其余患者均在医师指导下更改抗栓治疗方案，其中153例转为氯吡格雷联合阿司匹林抗血小板治疗，1例单独阿司匹林治疗。对完成6个月随访的PCI术后冠心病患者（n=499）分析发现，3个月内停用替格瑞洛患者发生主要缺血终点事件（4．58％VSO．82％，HR6．62，95％CI1．17－37．36，P=0．032）及联合缺血事件（11．45％VS4．89％，HR2．46，95％CI1．03～5．89，P=0．043）的风险均显著高于持续该药治疗的患者。两组患者联合出血终点事件的发生率差异无统计学意义（16．03％vs17．12％，HR0．92，95％C10．49～1．73，P=0．795）。结论替格瑞洛停药在冠心病患者中多见，院内及出院当天停药主要由于替格瑞洛相关呼吸困难、出血副作用及非复杂冠状动脉病变的PCI术，院外停药主要是无法获取药物和经济原因。与未停药患者相比，冠心病患者PCI术后3个月内停用该药可能增加主要缺血事件和联合缺血事件的发生风险。

Objective To analyze the reasons associated with ticagrelor withdrawal and the impact on clinical outcomes in ticagrelor-treated patients with coronary artery disease （CAD）. Methods Totally 642 consecutive CAD patients treated by ticagrelor and aspirin in the Department of Cardiology, Chinese PLA General Hospital from January 2014 to July 2015 were recruited. The incidence and the reasons of ticagrelor withdrawal were recorded and analyzed during the hospitalization, at discharge, as well as 3-month after discharge. In the patients treated by percutaneous coronary intervention （PCI）, the occurrence of ischemic events [including major ischemic events （cardiovascular death, non-fatal myocardial infarction, ischemic stroke, defined or probable stent thrombosis, coronary revascularization） and secondary ischemic events （readmission of unstable angina）] and bleeding events [including Thrombolysis In Myocardial Infarction trial （TIMI） defined major and minor bleedings] were followed up for 6 months. Results Ticagrelor withdrawal occurred in 164 patients （25.55%）, with 42 patients （25.61%） in-hospital, 7 patients（4.27%） at discharge and 115 patients （70.12%） after discharge, respectively. The distributions of ticagrelor withdrawal were 78.05% in unstable angina, 13.41% in ST-elevation myocardial infarction （STEMI）, 4.27% in non-STEMI, 4.27% in stable CAD, respectively. The reasons for ticagrelor withdrawal in-hospital and at discharge were mainly attributed to ticagrelor-related dyspnea （32.65%）, bleeding （22.45%） and PCI for non-complex coronary lesions （18.37%）. Drug unavailability （68.70%） and cost consideration （16.52%） were the major reasons for ticagrelor withdrawal after discharge. Besides 10 dead patients, other patients with ticagrelor withdrawal undertook the alteration of the antiplatelet therapy under the guidance of physicians, with 153 switched to clopidogrel on top of aspirin treatment, 1 to aspirin alone. After 6-month follow-up in PCI patients （n = 499）, compared with patients under continuous ticagrelor treatment, patients withdrawing ticagrelor had a higher risk of major ischemic events （4.58% vs 0.82%, HR 6.62, 95%CI 1.17-37.36, P= 0.032） and composited ischemic events （11.45% vs 4.89%, HR 2.46, and 95%CI 1.03-5.89, P = 0.043）. No significant difference was found for the risk of composited bleeding events between these patients （16.03% vs 17.12%, HR 0.92, and 95%CI, 0.49-1.73, P= 0.795）. Conelusion About one third of ticagrelor treated CAD patients undertake the ticagrelor withdrawal during hospitalization, discharge and within 3 months after hospitalization. Ticagrelor withdrawal in-hospital and at-discharge might be attributed mainly to ticagrelor-related dyspnea, bleeding and non-complex lesions for PCI. Drug unavailability and cost consideration might be the main reasons for out-hospital ticagrelor withdrawal. Ticagrelor withdrawal within 3-months in PCI treated CAD patients might be correlated with increased risk of major and composited ischemic events.