ACS患者血小板活性与预后无独立关联

美国心脏协会(AHA)年会上公布的TRILOGY研究的分支研究(TRILOGY ACS)显示，发生急性冠脉综合征(ACS)事件后，给予抗血小板药物进行治疗不能改善临床预后。普拉格雷组和氯吡格雷组的临床预后相似，这可能是由于血小板反应性与缺血性预后之间缺乏显著独立关联。该研究同时发表于《美国医学会杂志》(JAMA 2012;308:1785-94)。

Paul A. Gurbel博士

这项TRILOGY ACS血小板功能分支研究由西奈医院血栓研究中心主任Paul A. Gurbel博士及其同事进行，纳入仅接受药物治疗的ACS患者和需要置入≥1个冠脉支架的ACS患者。研究者对9,326例分别接受普拉格雷(Effient)和氯吡格雷(波利维)治疗的ACS患者的临床事件进行了比较。去年8月首次报告的总体研究的初步结果显示，接受这两种噻吩并吡啶类药物治疗的患者在临床终点方面无差异。

该分支研究纳入1,286例接受普拉格雷治疗的患者和1,278例接受氯吡格雷治疗的患者，在基线时、入组2 h后及1、 3、6、12、18、 24和 30个月时采用VerifyNow设备连续测定这些患者的血小板反应性。测定结果显示，在治疗开始后1个月内，与氯吡格雷组相比，普拉格雷组血小板反应性出现具有统计学意义的递增式降低，并且这种情况在研究的2.5年内持续存在。

单因素分析显示，血小板反应性的降低与30个月内临床事件数量的降低显著相关。然而，校正基线时的多个潜在混杂因素后发现，血小板反应性的程度与临床事件发生率无任何显著关联。

Gurbel博士表示，在该研究的接受药物治疗的非支架ACS患者中，导致缺血事件的其他因素可能包括内皮功能障碍和非血栓介导性缺血事件。在置入支架的患者中，缺血病理生理机制则较为单纯，在该机制中，P2Y12受体发挥重要作用。对Gurbel博士而言，该研究的最新结果表明，应在已接受经皮冠脉介入治疗和置入支架的ACS患者中，对普拉格雷和氯吡格雷治疗后的血小板反应性进行类似比较。

该研究获礼来和第一三共公司(普拉格雷经销商)资助。Gurbel博士声明是礼来和其他多家制药公司的顾问，并从这些公司获得研究资金。

相关评论：TRILOGY ACS留给我们的问题多于答案

Lars Wallentin博士

瑞典乌普萨拉大学临床研究中心主任Lars Wallentin博士表示，该分支研究的结果非常明确：普拉格雷可显著降低ADP诱导的血小板聚集。普拉格雷组约10%的患者具有高血小板反应性，而氯吡格雷组为50%。但更重要的是，研究者未发现血小板反应与临床预后之间存在独立关联。在未校正的分析中观察到这种关联，但在校正基线差异后，两者并无显著关联。

Wallentin博士表示，该分支研究结果表明，不能通过增加噻吩并吡啶类药物的剂量来降低风险，因此可尝试不同的药物，如通过使用替卡格雷(Brilinta)、试验性新药vorapaxar或抗凝剂等来优化ACS患者的药物治疗方案。

该研究留给我们的问题多于答案：为什么在该研究中，血小板反应性与临床预后之间无关联？这种缺乏关联的情况是否适用于其他P2Y12抑制剂(如替卡格雷)或其他类型的血小板抑制剂？如何解释在替卡格雷和vorapaxar用药者中观察到的预防作用？这些独特结果将如何影响未来研究和临床实践中血小板功能测定的应用？未来研究将如何研究通过强化血小板抑制来改善ACS患者的远期预后？

Wallentin博士是替卡格雷关节研究(PLATO研究)的主要研究者，从替卡格雷(Brilinta)经销商阿斯利康公司获得研究资金和其他经济利益，并且与其他一些制药公司存在经济利益关系。

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By: MITCHEL L. ZOLER, Cardiology News Digital Network

LOS ANGELES – Treatment proven to cut platelet reactivity in medically managed patients following an acute coronary syndrome event failed to improve clinical outcomes in a trial substudy with more than 2,500 patients, prompting experts to rethink their approach to managing patients with acute coronary disease who do not receive a coronary stent.

The "lack of a significant, independent association between platelet reactivity and ischemic outcomes may explain the comparable clinical outcomes" in the overall results of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, Dr. Paul A. Gurbel said at the annual scientific sessions of the American Heart Association.
 
"The value of platelet function testing will depend on the risk of the patient," said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore. He drew a distinction between the patients enrolled in TRILOGY ACS, which by design restricted enrolled acute coronary syndrome patients to only those targeted for exclusively medical management, and ACS patients who need to receive one or more coronary stents.

"In low-risk patients [those who don’t need a stent], it’s hard to do any change of treatment that improves outcomes, but we don’t have data on personalizing antiplatelet treatment for higher-risk patients," who require stenting, he said. "We know that in higher-risk patients, administering a more potent antiplatelet agent does have clinical benefit.

"I think the key is all about risk. The TRILOGY results clearly show that events occurred even at very low levels of platelet reactivity. That tells you something is driving these ischemic events beyond the interaction of ADP with a P2Y12 receptor," the action blocked by the two thienopyridines compared in TRILOGY ACS, prasugrel (Effient) and clopidogrel [Plavix], Dr. Gurbel said in an interview. "This pathway is very important, but it doesn’t seem to play a major role unless the patient has a stent."

Dr. Gurbel suggested that in the nonstented, medically managed ACS patients in TRILOGY ACS, other factors that might drive ischemic events could include endothelial dysfunction and nonthrombotic mediated ischemic events. "With patients who have stents, it’s a purer pathophysiology, where we know that the P2Y12 receptor plays an important role.

To Dr. Gurbel, the new findings he reported from the TRILOGY ACS substudy suggest that a similar comparison of platelet reactivity following prasugrel or clopidogrel treatment should be done in ACS patients who have undergone percutaneous coronary intervention and received a stent.
 
Dr. Lars Wallentin had a different take on the findings. He suggested that the way to optimize treatment in medically managed ACS patients is to "try something different," such as ticagrelor (Brilinta), the investigational agent vorapaxar, or an anticoagulant. The substudy results "show you can’t reduce risk by increasing the dose of a thienopyridine," said Dr. Wallentin, professor of medicine and director of the Clinical Research Center at Uppsala University in Sweden.

According to Dr. Wallentin, who made the following comments as the designated discussant for the TRILOGY ACS substudy, "The results of this substudy were very clear: Treatment with prasugrel substantially reduced ADP-induced platelet aggregation. About 10% of patients treated with prasugrel had high platelet reactivity, compared with about 50% of the clopidogrel-treated patients. But most important, the investigators showed no independent relationship between platelet activity, as measured by the device they used, and outcomes. There was a relation in an unadjusted analysis, but when corrected for baseline differences, there was no significant effect.

"The neutral outcome between prasugrel and clopidogrel seen in TRILOGY ACS contrasts with the consistent benefit seen with ticagrelor over clopidogrel in PLATO [Study of Platelet Inhibition and Patient Outcomes]," he said.

"The TRILOGY ACS substudy results leave us with more questions than answers: Why was there no association between platelet reactivity and outcomes in TRILOGY ACS? Would this lack of association also apply to other P2Y12 inhibitors, such as ticagrelor, or to other types of platelet inhibitors? How might the preventive effects seen with ticagrelor and vorapaxar be explained? And how should these unique results influence future use of platelet function measurement in either trials or in practice, and how should future trials address intensified platelet inhibition as a way to improve long-term outcomes in acute coronary syndrome patients?" Dr. Wallentin said.

The TRILOGY ACS platelet-function substudy piggybacked on a clinical-event comparison of prasugrel and clopidogrel in 9,326 ACS patients managed medically. Primary results from the overall trial, first reported last August, showed no difference in clinical end points between patients who received these two thienopyridines.

The prespecified substudy, which included 1,286 patients treated with prasugrel and 1,278 who received clopidogrel, involved serial measurements of platelet reactivity in these patients using VerifyNow devices, at baseline, after 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months into the study. These measurements showed that prasugrel treatment resulted in robust, statistically significant incremental reductions in platelet activity, compared with clopidogrel, within 1 month after the onset of treatment and continuing through the study’s 2.5 years.

In univariate analyses, reduced platelet reactivity significantly linked with reduced numbers of clinical events through 30 months. However, after adjustment for a long list of potential confounders at baseline, the degree of platelet reactivity failed to show any statistically significant relation to the incidence of clinical events, Dr. Gurbel reported.

Concurrent with his talk at the meeting, the findings appeared in an article published online (JAMA 2012;308:1785-94).

The TRILOGY ACS study was sponsored by Eli Lilly and Daiichi Sankyo, which market prasugrel. Dr. Gurbel said that he has been a consultant to and has received research grants from Eli Lilly and from several other drug companies. Dr. Wallentin served as lead investigator for PLATO, the pivotal trial of ticagrelor. He has received research funding and other financial benefit from AstraZeneca, the company that markets ticagrelor, and that he has served as a consultant to and has received research funding from several other drug companies.

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TRILOGY ACS Results in More Questions Than Answers

The results of this substudy were very clear: Treatment with prasugrel substantially reduced ADP-induced platelet aggregation. About 10% of patients treated with prasugrel had high platelet reactivity, compared with about 50% of the clopidogrel-treated patients. But most important, the investigators showed no independent relationship between platelet activity, as measured by the device they used, and outcomes. There was a relation in an unadjusted analysis, but when corrected for baseline differences, there was no significant effect.

The neutral outcome between prasugrel and clopidogrel seen in TRILOGY ACS contrasts with the consistent benefit seen with ticagrelor over clopidogrel in PLATO (Study of Platelet Inhibition and Patient Outcomes).

The TRILOGY ACS substudy results leave us with more questions than answers: Why was there no association between platelet reactivity and outcomes in TRILOGY ACS? Would this lack of association also apply to other P2Y12 inhibitors, such as ticagrelor, or to other types of platelet inhibitors? How might the preventive effects seen with ticagrelor and vorapaxar be explained? And how should these unique results influence future use of platelet function measurement in either trials or in practice, and how should future trials address intensified platelet inhibition as a way to improve long-term outcomes in acute coronary syndrome patients?

LARS WALLENTIN, M.D., is a professor of medicine and director of the Clinical Research Center at Uppsala University in Sweden. He served as lead investigator for the PLATO trial, the pivotal trial of ticagrelor. He has received research funding and other financial benefit from AstraZeneca, the company that markets ticagrelor (Brilinta), and that he has served as a consultant to and has received research funding from several other drug companies. Dr. Wallentin made these comments as the designated discussant for the TRILOGY ACS substudy.