每日2次给药可缓解糖尿病患者阿司匹林抵抗

巴黎——一项纳入92例患者的单中心交叉试验表明，在糖尿病合并冠状动脉疾病(CAD)患者中，阿司匹林每日2次给药方案阻断血小板聚集的效果明显优于总剂量相同的每日1次给药方案。

在欧洲经皮心血管介入学会(EAPCI)2013年会上，法国巴黎Lariboisière医院心脏科的Jean-Guillaume Dillinger医生报告称，与未患糖尿病的患者相比，糖尿病患者往往对心血管事件二级预防中的阿司匹林治疗应答较差，这显然是因为在糖尿病患者中血小板更新得更快。由于阿司匹林给药后足以抑制血小板聚集的血药浓度只能维持2 h左右，因此血小板更新加快会导致只有少量的血小板暴露于足够浓度的阿司匹林，从而加重阿司匹林抵抗，血栓形成的风险也更高。


Jean-Guillaume Dillinger医生
 
Dillinger医生等人共纳入了92例已经开始接受阿司匹林治疗的糖尿病合并血管造影确诊CAD的患者。所有受试者都是在30岁以后首次被确诊为糖尿病，并且当时没有接受胰岛素作为初始治疗，除非是在急性冠脉综合征发作期间开始治疗的。此外，所有受试者至少存在下列其他危险因素中的1项：当前吸烟者、超敏C-反应蛋白(hsCRP)水平高于4 mg/L、纤维蛋白原水平高于4 g/L、或者血小板计数大于270,000/mm³。

受试者的平均年龄为64岁，男性占85%，平均在糖尿病确诊后12年参与该试验。在这92例患者中，48%存在1项危险因素，30%存在2项，15%存在3项，7%存在所有4项危险因素。48例患者(52%)在入组时正在接受每日1次氯吡格雷治疗，试验中允许继续接受这种治疗。

这些受试者被随机分配至阿司匹林150 mg组(每日清晨服用，连续服用7~14天后抽取血样)或者阿司匹林75 mg组(清晨服用1次，晚上服用1次，连续服用7~14天后抽取血样)。采血后，受试者立即交换给药方案，再连续服用7~14天，然后进行第二次采血。

研究者采用光透集合度测定法检测了每份血样的血小板聚集情况以评估阿司匹林抵抗。最大聚集率≥20%的血样被视为存在阿司匹林抵抗。

检测结果显示，在接受阿司匹林每日1次治疗时有39例患者(42%)出现了阿司匹林抵抗，而在接受每日2次给药方案时只有16例患者(17%)出现了阿司匹林抵抗，差异有统计学意义。

Dillinger医生报告称，当这39例在接受每日1次给药方案期间出现阿司匹林抵抗的受试者改为每日2次方案后，有24例对阿司匹林产生了应答。相反，当这16例在每日2次治疗期间出现阿司匹林抵抗的受试者改为每日1次方案后，只有1例产生应答。

研究者还采用血小板功能分析仪评价了反映血小板功能的第二项指标——整体血小板活性。检测结果显示，38例患者(41%)在接受每日1次阿司匹林治疗期间血小板活性正常，而在接受每日2次治疗期间只有27例患者(29%)血小板活性正常。在由只对一种给药方案产生抵抗的27例患者组成的亚组中，19例(70%)在改成每日2次方案后对阿司匹林产生了应答，8例在改成每日1次方案后产生了应答，差异有统计学意义。

氯吡格雷治疗对给药频率与阿司匹林抗血小板效应之间的关系无明显影响。

针对可能影响阿司匹林抗血小板效应的因素开展的多变量分析表明，与每日1次治疗相比，每日2次治疗与阿司匹林抵抗发生率下降79%相关，差异有统计学意义。此外，只有一项其他参数对阿司匹林抵抗有显著影响，即hsCRP水平。hsCRP每升高1 mg/L，阿司匹林抵抗发生率即增加15%。

Dillinger医生说：“我们的研究结果提供了一种解决糖尿病患者生物学阿司匹林抵抗的新办法。”但他也提醒道：“尚需开展大规模前瞻性试验以评估阿司匹林每日2次治疗是否能降低动脉粥样硬化性血栓形成事件的发生率并且不增加消化道毒性等副作用。”每日2次给药方案的另一个潜在缺点是患者依从性可能会下降。

Dillinger博士还强调，该试验纳入的都是至少还存在1项阿司匹林失效危险因素的糖尿病患者：吸烟和(或)炎性标志物水平升高，因此“试验结果不能外推至整个糖尿病合并CAD的患者群”。但他估计超过一半的糖尿病合并CAD患者很可能至少存在1项这样的危险因素。

美国佛罗里达大学心血管研究与血栓形成研究中心主任Dominick J. Angiolillo博士评论道：“这项药效学研究结果表明，与阿司匹林每日1次给药方案相比，每日2次方案可能更好地发挥抗血小板效应，这与之前的研究结果相符。”他在接受采访时表示：“研究数据证明了每日2次方案是改善治疗应答的一种有效策略，但这毕竟是一项药效学研究，因此尚不能就这种方案的临床疗效和安全性得出结论。未来还需要开展相应的临床研究以指导临床实践。”


Dominjick Angiolillo博士

Dillinger医生已就该研究结果发表了一篇论文(Am. Heart J. 2012;164:600-6)。

Dillinger医生声明称无相关利益冲突。Angiolillo博士声明称接受了百时美-施贵宝、赛诺菲-安万特、礼来等多家药品和医疗器械企业提供的酬金。

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By: MITCHEL L. ZOLER, Cardiology News Digital Network

PARIS – Twice-daily dosing with aspirin worked substantially better for blocking platelet aggregation than did once-daily treatment with the same total dosage, in patients with diabetes and coronary artery disease in a single-center crossover study with 92 patients.

Patients with diabetes are often less responsive to aspirin treatment for secondary prevention of cardiovascular events than are patients without diabetes, apparently because of faster platelet turnover in patients with diabetes, Dr. Jean-Guillaume Dillinger said at the annual meeting of the European Association for Percutaneous Cardiovascular Interventions. Because aspirin levels sufficient to dampen platelet aggregation persist only for about 2 hours following a dose, faster platelet turnover leads to fewer platelets exposed to an adequate aspirin level, increased aspirin resistance, and greater thrombotic potential.

"The results of our study offer a new option to overcome biological aspirin resistance in patients with diabetes," said Dr. Dillinger, a cardiologist at Lariboisière Hospital in Paris. But Dr. Dillinger also cautioned that "large, prospective trials are needed to test if aspirin twice daily can decrease the rate of atherothrombotic events without increasing side effects such as gastrointestinal toxicity." Another potential drawback of twice-daily dosing is that patient compliance with the regimen may be reduced.

Dr. Dillinger also stressed that his study specifically enrolled patients with diabetes with at least one additional risk factor for loss of aspirin efficacy: They were either smokers or had elevated inflammatory markers, and hence, "the results cannot be extrapolated to the whole population of patients with diabetes and coronary artery disease." But he estimated that more than half of patients with diabetes and coronary artery disease (CAD) likely have at least one of these increased-risk factors.

"The results from Dr. Dillinger’s pharmacodynamic study show that a twice-daily regimen may offer greater antiplatelet effects than once daily and are in line with the results from prior investigations," commented Dr. Dominick J. Angiolillo, director of the Cardiovascular Research and Thrombosis Research Center at the University of Florida in Jacksonville. "The data support that [a twice-daily] regimen can be an effective strategy to improve response profiles, but this was a pharmacodynamic study and no conclusions can be made from the results on its clinical efficacy of safety. Clinical studies are warranted to support a change in practice," he said in an interview.
 
Dr. Dillinger and his associates enrolled 92 patients with diabetes and angiography-confirmed CAD who were already on aspirin treatment. All patients had been first diagnosed with diabetes after they were 30 years old, and they had not received insulin as their initial diabetes treatment unless their treatment had begun during an episode of acute coronary syndrome. In addition, all enrolled patients had at least one of these additional risk factors: current smoker, a high-sensitivity C-reaction protein (hsCRP) level of more than 4 mg/L, a fibrinogen level of more than 4 g/L, or a platelet count of more than 270,000/mm3.

The patients averaged 64 years old, 85% were men, and they entered the study an average of 12 years following their diabetes diagnosis. Of the 92 patients, 48% had one high-risk marker, 30% had two, 15% had three, and 7% had all four of the high-risk markers. Forty-eight (52%) of the patients entered the study on a daily clopidogrel regimen, and that treatment continued.

Patients were randomized to receive either 150 mg aspirin once daily taken every morning for 7-14 days before blood sampling, or 75 mg of aspirin taken twice daily, once in the morning and once in the evening for 7-14 days before their blood was drawn. Following the blood draw, they immediately switched to the alternative regimen that again continued for 7-14 days before the researchers took a second blood sample.

They assessed aspirin resistance by measuring platelet aggregation of each blood specimen using light transmission aggregometry. Specimens that produced a maximum aggregation intensity of at least 20% were considered to indicate aspirin resistance.

Testing revealed aspirin resistance in 39 (42%) patients when the study group received aspirin once daily, and in 16 patients (17%) when they were on the twice-daily regimen, a statistically significant difference.

When the 39 patients who showed aspirin resistance on the once-daily dosage were switched to twice-daily, 24 became aspirin responders on the twice-daily schedule. In contrast, among the 16 patients who were aspirin resistant on twice-daily treatment, 1 patient became responsive on the once-daily regimen, Dr. Dillinger reported.

The researchers also applied a second measure of platelet function – global platelet reactivity – using a platelet function analyzer. By this measure, they found that 38 (41%) of patients had normal platelet reactivity with once-daily aspirin, compared with 27 (29%) when patients were on twice-daily treatment. Within the subgroup of 27 patients who were resistant on either of the two regimens but not the other, 19 (70%) became responders when switched to the bid regimen, with 8 (30%) becoming responders when switched to once daily, a statistically significant difference between the two regimens.

Clopidogrel treatment had no discernable impact on the links between dosing frequency and aspirin’s antiplatelet effects.

A multivariate analysis of factors potentially affecting aspirin’s antiplatelet effect found that twice-daily treatment linked with a statistically significant 79% cut in the likelihood of aspirin resistance, compared with once daily. The only other parameter measured with a significant impact on aspirin resistance in this analysis was level of hsCRP. Every 1 mg/L rise in hsCRP linked with a 15% increased rate of resistance.

Dr. Dillinger also reported these findings in a published article (Am. Heart J. 2012;164:600-6)

Dr. Dillinger had no disclosures. Dr. Angiolillo said that he has received honoraria from several drug and device companies including Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly, and others. He has also received research grants from several companies