Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, Padova, Italy.
Azienda Sanitaria Friuli Occidentale, Ospedale Santa Maria degli Angeli, Pordenone, Italy.
J Am Coll Cardiol. 2020 Nov 24;76(21):2450-2459. doi: 10.1016/j.jacc.2020.08.053. Epub 2020 Aug 31.
Although oral P2Y inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined.
The purpose of this study was to compare downstream and upstream oral P2Y inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment.
We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit).
We randomized 1,449 patients to downstream or upstream oral P2Y inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment).
Downstream and upstream oral P2Y inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837).
尽管口服 P2Y 抑制剂是治疗非 ST 段抬高型急性冠状动脉综合征患者的关键药物，但它们的最佳给药时间尚未明确。
本研究旨在比较经皮冠状动脉介入治疗患者中应用下游和上游口服 P2Y 抑制剂的治疗策略。
我们进行了一项随机、适应性、开放标签、多中心临床试验。患者被随机分为接受血管造影前替格瑞洛预处理（上游组）或不预处理（下游组）。下游组行经皮冠状动脉介入治疗的患者进一步随机接受替格瑞洛或普拉格雷治疗。主要假设是下游策略优于上游策略，表现在疗效和安全性事件的综合终点（净临床获益）上。
我们将 1449 例患者随机分配至下游或上游口服 P2Y 抑制剂给药组。中期分析时预先设定的无效性终止规则导致试验提前终止。主要终点（血管原因导致的死亡；非致死性心肌梗死或非致死性卒中和 Bleeding Academic Research Consortium 3、4 和 5 型出血的复合终点）在下游组和上游组之间的发生率无显著差异（绝对风险降低率：-0.46%；95%重复置信区间：-2.90%至 1.90%）。这些结果在接受经皮冠状动脉介入治疗的患者（人群的 72%）和无论冠状动脉造影时间（入组后 24 小时内或之后）如何都得到了证实。
下游和上游口服 P2Y 抑制剂给药策略与缺血和出血事件发生率低有关，且治疗组之间的事件发生率差异很小。这些发现导致试验提前中断，并提示一种策略优于另一种策略的可能性不大。（初始有创指征的非 ST 段抬高型急性冠状动脉综合征患者中 P2Y 受体阻滞剂的下游与上游给药策略：DUBIUS 试验；NCT02618837）
