一项随机、安慰剂对照交叉试验,以评估体重对阿司匹林触发的专门促和解介质的影响:发现研究方案

Natalie G. McGowan, Judy H. Zhong, L. Trasande, Jason Hellmann, Sean P. Heffron
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引用次数: 0

摘要

背景:小剂量阿司匹林对体重超过 70 公斤的人心血管事件的一级预防无效。虽然普遍的解释是体重越大,血小板环氧合酶-1(COX-1)的抑制作用越弱,但支持这一观点的数据有限,因此需要进一步研究其背后的原因。我们认为,阿司匹林介导的环氧合酶-2(COX-2)乙酰化和由此产生的 15-epi-lipoxin A4(一种专门的促溶解介质)的合成在体重较高的人中处于次优状态,这可能是临床试验结果的原因:为了验证这一假设,我们正在进行一项双盲、安慰剂对照、随机、机理交叉试验。体重不等的健康男性和女性分别服用 81 毫克阿司匹林和 325 毫克阿司匹林 3 周,然后进行为期 3 周的安慰剂磨合和冲洗。我们的目标样本量为 90 名受试者,估计至少需要 72 名受试者完成所有访问,才能获得足够的力量来检验我们的主要假设。我们的主要终点是血浆中 15-epi-lipoxin A4 在每次服用阿司匹林后的变化差异。次要终点包括脂质介质谱、血清生物活性脂质谱以及与血管炎症消退有关的其他终点:该研究于 2021 年 11 月开始招生,目前仍在进行中。这项研究的结果将使我们更好地了解阿司匹林在预防不良心血管后果中的作用机制。这些结果还可能引发更多研究,为根据体重制定患者用药策略提供依据:本试验已在 ClinicalTrials.gov 注册,标识符为 NCT04697719。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A randomized, placebo-controlled crossover trial to assess the influence of body weight on aspirin-triggered specialized pro-resolving mediators: protocol for the discover study
Background: Low-dose aspirin is ineffective for primary prevention of cardiovascular events in people with body weight greater than 70kg. While the prevalent explanation for this is reduced platelet cyclooxygenase-1 (COX-1) inhibition at higher body weights, supporting data are limited, thereby demanding further investigation of the reason(s) underlying this observation. We propose that aspirin-mediated cyclooxygenase-2 (COX-2) acetylation and the resulting synthesis of 15-epi-lipoxin A4, a specialized pro-resolving mediator, is suboptimal in higher weight individuals, which may contribute to the clinical trial findings. Methods: To test this hypothesis, we are conducting a double-blind, placebo-controlled, randomized, mechanistic crossover trial. Healthy men and women exhibiting a wide range of body weights take 81mg aspirin and 325mg aspirin for 3 weeks each, following 3-week placebo run-in and wash-out phases. Our target sample size is 90 subjects, with a minimum of 72 completing all visits estimated to be necessary to achieve power adequate to test our primary hypothesis. Our primary endpoint is the difference in change in plasma 15-epi-lipoxin A4 occurring with each dose of aspirin. Secondary endpoints include lipid mediator profiles, serum bioactive lipid profiles, and other endpoints involved in the resolution of vascular inflammation. Conclusions: Study enrollment began in November 2021 and is ongoing. The results of this study will improve our understanding of the mechanisms underlying aspirin’s role(s) in the prevention of adverse cardiovascular outcomes. They may also lead to additional studies with the potential to inform dosing strategies for patients based on body weight. Trial registration: This trial is registered with ClinicalTrials.gov identifier NCT04697719.
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