Background

Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor.

Methods

The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population).

Findings

Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p _interaction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, p _interaction=0·012. Benefit was present irrespective of time from most recent PCI.

Interpretation

In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk.

Funding

AstraZeneca.

中文翻译：

---

具有既往经皮冠状动脉介入治疗史（THEMIS-PCI）的糖尿病和稳定冠状动脉疾病患者的替卡格雷治疗：一项3期，安慰剂对照，随机试验。

背景

先前经皮冠状动脉介入治疗（PCI）的患有稳定型冠状动脉疾病和糖尿病的患者，尤其是先前采用支架置入术的患者，发生缺血性事件的风险很高。这些患者通常接受阿司匹林治疗。在该试验中，我们旨在研究这些患者是否将从阿司匹林加替卡格雷的治疗中受益。

方法

替卡格雷对糖尿病患者健康结局的影响干预研究（THEMIS）是一项在42个国家的1315个地点进行的3期随机，双盲，安慰剂对照试验。如果患者为50岁或50岁以上，患有2型糖尿病，接受降血糖药至少6个月，患有稳定的冠状动脉疾病以及其他三个互不排斥的标准之一，则有资格：既往有PCI或冠状动脉病史动脉旁路移植术，或至少一根冠状动脉的血管造影狭窄记录为50％或更多。通过使用交互式语音响应或网络响应系统，将符合条件的患者随机分配（1：1）替卡格雷或安慰剂。THEMIS-PCI试验包括先前有PCI的患者的一个预先指定的亚组。

发现

在2014年2月17日至2016年5月24日之间，THEMIS-PCI试验招募了11 154名具有先前PCI病史的患者（占整个THEMIS试验的58％）。中位随访时间为3·3年（IQR 2·8–3·8）。在先前的PCI组中，接受替格瑞洛治疗的主要疗效结果事件的患者少于安慰剂组（5558的404 [7·3％] vs 5596的480 [8·6％]； HR 0·85 [95％CI] 0·74-0·97]，p = 0·013）。没有PCI的患者未观察到相同的效果（p = 0·76，p_交互作用= 0·16）。在两个治疗组中，心血管死亡患者的比例相似（替卡格雷组为174 [3·1％] ，安慰剂组为183 [3·3％]； HR 0·96 [95％CI 0·78-1·18] ，p = 0·68）以及全因死亡（282 [5·1％] vs323 [5·8％]; 0·88 [0·75-1·03]，p = 0·11）。TIMI大出血发生在接受替卡格雷的5536例患者中的111（2·0％）和接受安慰剂的5564例患者中的62（1·1％）（HR 2·03 [95％CI 1·48-2·76]，p < 0·0001）和5536例替格瑞洛患者中的6（0·1％）致命出血和5564安慰剂患者中的6（0·1％）（1·13 [0·36–3·50]，p = 0 ·83）。颅内出血发生在33例（0·6％）和31例（0·6％）患者中（1·21 [0·74-1·97]，p = 0·45）。替卡格雷改善的临床净收益：519/5558（9·3％）对617/5596（11·0％），HR = 0·85，95％CI 0·75–0·95，p = 0·005与没有PCI的患者相反，p_交互作用= 0·012。无论从最近的PCI抽出时间如何，都可以受益。

解释

在患有糖尿病，稳定的冠状动脉疾病和以前的PCI的患者中，替卡瑞洛联合阿司匹林可减少心血管死亡，心肌梗塞和中风，尽管增加了大出血量。在这么大且易于识别的人群中，替卡格雷洛提供了有利的净临床收益（比没有PCI史的患者要多）。这种效果表明，对于患有糖尿病且具有抗血小板治疗耐受性，缺血风险高，出血风险低的PCI史的患者，应考虑除阿司匹林外还应长期使用替卡格雷治疗。

资金

阿斯利康。