Serebruany Victor L, Ziai Wendy, Cabrera-Fuentes Hector A, Pokov Brendon, Hwang Isabella, Marciniak Thomas
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
HeartDrug Research LLC, West Friendship, MD 21294, USA.
Rev Cardiovasc Med. 2025 Apr 27;26(4):36733. doi: 10.31083/RCM36733. eCollection 2025 Apr.
This study aimed to determine the impact of central adjudication of site-reported events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in addition to aspirin within the frame of indication-seeking The PLATelet Inhibition and Clinical Outcomes (PLATO) trial. Adjudication in randomized outcome-driven trials is supposed to maintain integrity by applying uniform rules for the quality assessment of clinical events. Some preliminary data suggest an imbalance between central and site diagnoses in PLATO. We gained access to the Food and Drug Administration (FDA)-issued adjudication dataset and analyzed the evidence.
Death, myocardial infarction (MI), stroke/ transient ischemic attack (TIA), bleeding, arterial thrombotic events, and cardiac ischemic events underwent central adjudication. We assessed geography, timing, impact of disagreements, and primary endpoint composition.
Among 18,624 trial enrollees, 10,704 central adjudications occurred across 7171 patients in 43 countries. There were 938 deaths, 2751 cases of MI, 359 strokes/TIAs, 2680 cardiac events, 130 thrombotic events, and 3782 bleeding events. The match occurred for 5451 events, while mismatches favoring clopidogrel (n = 2535) or ticagrelor (n = 2706) ( = 0.79) were common for major (n = 1797), moderate (n = 942), or minor (n = 735) disagreements. The central decision prevailed in 2945 cases. There was a significant (HR = 0.84; 95% confidence intervals (CI): 0.75-0.95; = 0.004) adjudication delay in the 2007-2008 events but finalized in 2009. Ticagrelor was significantly less favored in 2009 than in 2007-2008 (HR = 1.19; 95% CI: 1.05-1.34; = 0.005). There was a remarkably consistent match for bleeding adjudication (HR = 1.02; 95% CI: 0.83-1.25; = 0.859) between treatment arms. The primary endpoint in the PLATO trial exhibited highly significant disagreement favoring ticagrelor for vascular death (HR = 2.02; 95% CI: 1.1-3.64; = 0.019); MI (HR = 2.31; 95% CI: 2.79-43.94; = 0.034); stroke (HR = 1.37; 95% CI: 2.66-63.28; = 0.036); total events (HR = 2.51; 95% CI: 1.86-3.39; = 0.01).
Central adjudication in the PLATO trial was delayed and impacted the primary endpoint by inflating the ticagrelor benefit, resulting in drug approval. The regulatory authorities should consider independent audits when unblinding is suspected in the indication-seeking clinical trials.
本研究旨在确定在“血小板抑制与临床结果（PLATO）”试验的探索性适应症范围内，对接受替格瑞洛或氯吡格雷联合阿司匹林治疗的急性冠状动脉综合征患者，由中心判定各研究点报告事件的影响。在随机结果驱动的试验中，判定旨在通过应用统一规则对临床事件进行质量评估来保持完整性。一些初步数据表明PLATO试验中中心诊断与研究点诊断之间存在不平衡。我们获取了美国食品药品监督管理局（FDA）发布的判定数据集并分析了相关证据。
对死亡、心肌梗死（MI）、中风/短暂性脑缺血发作（TIA）、出血、动脉血栓形成事件和心脏缺血事件进行中心判定。我们评估了地域、时间、分歧的影响以及主要终点的构成。
在18624名试验参与者中，43个国家的7171名患者进行了10704次中心判定。有938例死亡、2751例MI、359例中风/TIA、2680例心脏事件、130例血栓形成事件和3782例出血事件。5451个事件判定结果相符，而对于主要（n = 1797）、中度（n = 942）或轻度（n = 735）分歧，判定结果不相符且更倾向于氯吡格雷（n = 2535）或替格瑞洛（n = 2706）（κ = 0.79）的情况很常见。2945例中中心判定结果占主导。2007 - 2008年的事件存在显著的判定延迟（HR = 0.84；95%置信区间（CI）：0.75 - 0.95；P = 0.004），但在2009年完成判定。2009年替格瑞洛相比2007 - 2008年明显不占优势（HR = 1.19；95% CI：1.05 - 1.34；P = 0.005）。治疗组之间出血判定结果有非常一致的相符情况（HR = 1.02；95% CI：0.83 - 1.25；P = 0.859）。PLATO试验的主要终点在血管性死亡（HR = 2.02；95% CI：1.1 - 3.64；P = 0.019）、MI（HR = 2.31；95% CI：2.79 - 43.94；P = 0.034）、中风（HR = 1.37；95% CI：2.66 - 63.28；P = 0.036）、总事件（HR = 2.51；95% CI：1.86 - 3.39；P = 0.01）方面存在高度显著的判定分歧，更倾向于替格瑞洛。
PLATO试验中的中心判定出现延迟，并通过夸大替格瑞洛的益处影响了主要终点，从而导致药物获批。监管机构在怀疑探索性临床试验存在揭盲情况时应考虑进行独立审计。
