BACKGROUND Current guidelines recommend potent platelet inhibition with ticagrelor or prasugrel in patients after an acute coronary syndrome. However, data about optimal platelet inhibition in older patients are scarce. We aimed to investigate the safety and efficacy of clopidogrel compared with ticagrelor or prasugrel in older patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS We did the open-label, randomised controlled POPular AGE trial in 12 sites (ten hospitals and two university hospitals) in the Netherlands. Patients aged 70 years or older with NSTE-ACS were enrolled and randomly assigned in a 1:1 ratio using an internet-based randomisation procedure with block sizes of six to receive a loading dose of clopidogrel 300 mg or 600 mg, or ticagrelor 180 mg or prasugrel 60 mg, and then a maintenance dose for the duration of 12 months (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily) on top of standard care. Patient and treating physicians were aware of the allocated treatment strategy, but the outcome assessors were masked to treatment allocation. Primary bleeding outcome consisted of PLATelet inhibition and patient Outcomes (PLATO; major or minor bleeding [superiority hypothesis]). Co-primary net clinical benefit outcome consisted of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding (non-inferiority hypothesis, margin of 2%). Follow-up duration was 12 months. Analyses were done on intention-to-treat basis. This trial is registered with the Netherlands Trial Register (NL3804), ClinicalTrials.gov (NCT02317198), and EudraCT (2013-001403-37). FINDINGS Between June 10, 2013, and Oct 17, 2018, 1002 patients were randomly assigned to clopidogrel (n=500) or ticagrelor or prasugrel (n=502). Because 475 (95%) patients received ticagrelor in the ticagrelor or prasugrel group, we will refer to this group as the ticagrelor group. Premature discontinuation of the study drug occurred in 238 (47%) of 502 ticagrelor group patients randomly assigned to ticagrelor, and in 112 (22%) of 500 patients randomly assigned to clopidogrel. Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; hazard ratio 0·71, 95% CI 0·54 to 0·94; p=0·02 for superiority). Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; absolute risk difference -4%, 95% CI -10·0 to 1·4; p=0·03 for non-inferiority). The most important reasons for discontinuation were occurrence of bleeding (n=38), dyspnoea (n=40), and the need for treatment with oral anticoagulation (n=35). INTERPRETATION In patients aged 70 years or older presenting with NSTE-ACS, clopidogrel is a favourable alternative to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke, and bleeding. Clopidogrel could be an alternative P2Y12 inhibitor especially for elderly patients with a higher bleeding risk. FUNDING ZonMw.

中文翻译：

---

患有非ST抬高的急性冠状动脉综合征（POPular AGE）的70岁或以上患者的氯吡格雷与替卡格雷或普拉格雷的比较：这项随机，开放标签，非劣效性试验。

背景技术当前的指南建议在急性冠状动脉综合征后患者中用替格瑞洛或普拉格雷有效地抑制血小板。但是，关于老年患者最佳血小板抑制作用的数据很少。我们旨在研究氯吡格雷与替卡格雷或普拉格雷相比在非ST抬高急性冠脉综合征（NSTE-ACS）老年患者中的安全性和有效性。方法我们在荷兰的12个地点（十家医院和两家大学医院）进行了开放标签，随机对照POPular AGE试验。纳入年龄为70岁或70岁以上的NSTE-ACS患者，并使用基于互联网的随机程序以1：1的比例随机分配，其块大小为6，以接受300 mg或600 mg的氯吡格雷或ticagrelor 180 mg的负荷剂量或普拉格雷60毫克，然后在标准护理上维持12个月的维持剂量（氯吡格雷75毫克每天一次，替卡格雷90毫克每天两次，普拉格雷10毫克每天一次）。病人和主治医生都知道分配的治疗策略，但是结果评估者对治疗分配不了解。原发性出血结局包括PLATelet抑制和患者预后（PLATO；主要或次要出血[优势假设]）。共同主要临床净获益结局包括全因死亡，心肌梗塞，中风，PLATO大出血和小出血（非劣效性假设，边际率为2％）。随访时间为12个月。在意向性治疗的基础上进行了分析。该试验已在荷兰试验注册（NL3804），ClinicalTrials.gov（NCT02317198）和EudraCT（2013-001403-37）中进行了注册。结果在2013年6月10日至2018年10月17日之间，将1002例患者随机分配给氯吡格雷（n = 500）或替卡格雷或普拉格雷（n = 502）。由于在替卡格雷或普拉格雷组中有475位患者（95％）接受了替卡格雷治疗，因此我们将这一组称为替卡格雷治疗组。随机分配给替卡格雷的502替卡格雷组患者中有238名（47％）接受研究药物的过早停用，随机分配给氯吡格雷的500例患者中有112名（22％）。氯吡格雷组的原发性出血结果（500名患者中的88 [18％]）显着低于替卡格雷组（502的118 [24％]）；危险比0·71，95％CI 0·54至0·94 ； p = 0·02为优势）。氯吡格雷（139 [28％]）与替卡格雷（161 [32％]；绝对风险差异-4％，95％CI -10·0至1·4；p = 0·03（非自卑）。停药的最重要原因是出血（n = 38），呼吸困难（n = 40）和需要口服抗凝治疗（n = 35）。解释对于70岁以上NSTE-ACS的患者，氯吡格雷是替卡格雷的替代药物，因为它可以减少出血事件，而不会增加全因死亡，心肌梗塞，中风和出血的合并终点。氯吡格雷可能是一种替代的P2Y12抑制剂，特别是对于出血风险较高的老年患者。资助ZonMw。解释对于70岁或以上患有NSTE-ACS的患者，氯吡格雷是替卡格雷的一种替代选择，因为它可以减少出血事件，而不会增加全因死亡，心肌梗塞，中风和出血的综合终点。氯吡格雷可能是一种替代的P2Y12抑制剂，特别是对于出血风险较高的老年患者。资助ZonMw。解释对于70岁以上NSTE-ACS的患者，氯吡格雷是替卡格雷的替代药物，因为它可以减少出血事件，而不会增加全因死亡，心肌梗塞，中风和出血的合并终点。氯吡格雷可能是一种替代的P2Y12抑制剂，特别是对于出血风险较高的老年患者。资助ZonMw。