Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts.
Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.
J Am Coll Cardiol. 2017 Feb 14;69(6):603-612. doi: 10.1016/j.jacc.2016.11.050. Epub 2017 Jan 11.
A limitation of aspirin is that some patients, particularly those with diabetes, may not have an optimal antiplatelet effect.
The goal of this study was to determine if oral bioavailability mediates nonresponsiveness.
The rate and extent of serum thromboxane generation and aspirin pharmacokinetics were measured in 40 patients with diabetes in a randomized, single-blind, triple-crossover study. Patients were exposed to three 325-mg aspirin formulations: plain aspirin, PL2200 (a modified-release lipid-based aspirin), and a delayed-release enteric-coated (EC) aspirin. Onset of antiplatelet activity was determined by the rate and extent of inhibition of serum thromboxane B (TXB) generation. Aspirin nonresponsiveness was defined as a level of residual serum TXB associated with elevated thrombotic risk (<99.0% inhibition or TXB >3.1 ng/ml) within 72 h after 3 daily aspirin doses.
The rate of aspirin nonresponsiveness was 15.8%, 8.1%, and 52.8% for plain aspirin, PL2200, and EC aspirin, respectively (p < 0.001 for both comparisons vs. EC aspirin; p = 0.30 for comparison between plain aspirin and PL2200). Similarly, 56% of EC aspirin-treated subjects had serum TXB levels >3.1 ng/ml, compared with 18% and 11% of subjects after administration of plain aspirin and PL2200 (p < 0.0001). Compared with findings for plain aspirin and PL2200, this high rate of nonresponsiveness with EC aspirin was associated with lower exposure to acetylsalicylic acid (63% and 70% lower geometric mean maximum plasma concentration [C] and 77% and 82% lower AUC [area under the curve from time 0 to the last time measured]) and 66% and 72% lower maximum decrease of TXB, with marked interindividual variability.
A high proportion of patients treated with EC aspirin failed to achieve complete inhibition of TXB generation due to incomplete absorption. Reduced bioavailability may contribute to "aspirin resistance" in patients with diabetes. (Pharmacodynamic Evaluation of PL2200 Versus Enteric-Coated and Immediate Release Aspirin in Diabetic Patients; NCT01515657).
阿司匹林的一个局限性在于，一些患者，尤其是糖尿病患者，可能无法达到最佳的抗血小板作用。
本研究旨在确定口服生物利用度是否介导了无应答。
在一项随机、单盲、三交叉研究中，对 40 例糖尿病患者测量了血清血栓素生成的速率和程度以及阿司匹林的药代动力学。患者暴露于三种 325 毫克阿司匹林制剂：普通阿司匹林、PL2200（一种改良释放的基于脂质的阿司匹林）和延迟释放肠溶阿司匹林。通过抑制血清血栓素 B（TXB）生成的速率和程度来确定抗血小板活性的起始时间。阿司匹林无应答定义为在每日 3 次阿司匹林剂量后 72 小时内与升高的血栓形成风险相关的残留血清 TXB 水平（<99.0%抑制或 TXB >3.1ng/ml）。
普通阿司匹林、PL2200 和肠溶阿司匹林的阿司匹林无应答率分别为 15.8%、8.1%和 52.8%（与肠溶阿司匹林相比，均 p<0.001；与普通阿司匹林相比，p=0.30）。同样，56%的肠溶阿司匹林治疗患者的血清 TXB 水平>3.1ng/ml，而普通阿司匹林和 PL2200 治疗的患者分别为 18%和 11%（p<0.0001）。与普通阿司匹林和 PL2200 相比，这种肠溶阿司匹林的高无应答率与较低的乙酰水杨酸暴露相关（几何均数最大血浆浓度 [C]分别低 63%和 70%，曲线下面积 [AUC]分别低 77%和 82%），TXB 的最大下降率也低 66%和 72%，个体间存在明显差异。
由于吸收不完全，接受肠溶阿司匹林治疗的患者中很大比例未能完全抑制 TXB 的生成，导致无法达到完全抑制 TXB 的生成。生物利用度降低可能导致糖尿病患者出现“阿司匹林抵抗”。（PL2200 与肠溶和普通阿司匹林在糖尿病患者中的药效学评价；NCT01515657）。
