NSTE-ACS：普拉格雷预治疗增加出血风险

随机对照的Ⅲ期ACCOAST试验结果显示，接受P2Y12拮抗剂普拉格雷治疗的非ST段抬高性急性心肌冠脉综合征(NSTE-ACS)患者的主要缺血事件发生率并未降低，冠脉造影后30天内的主要出血并发症发生率反而增加。

法国巴黎Pitié-Salpêtrière大学中心医院心脏病研究所的Gilles Montalescot医生在欧洲心脏病学会(ESC)年会上报告称，主要疗效终点——7天内的心血管原因死亡、心肌梗死、卒中、紧急血管重建或糖蛋白Ⅱb/Ⅲa抑制剂挽救治疗的复合终点——在血管造影前后使用普拉格雷组(预治疗组，n=2,037)和仅血管造影后使用普拉格雷组(对照组，n=1,996)中相似[10.0% vs. 9.8%；危险比(HR)，1.02]。

接受经皮冠脉介入(PCI)治疗的患者的主要复合终点发生率也与最终接受了PCI、冠脉旁路移植术(CABG)或仅接受内科治疗的所有患者相似。

然而，在关键安全性终点——7天内心肌梗死溶栓(TIMI)主要出血事件——的发生率方面，预治疗组高于对照组(2.6% vs. 1.4%；HR，1.90)。并且这一差异在30天时仍然存在。该研究结果同时发表在《新英格兰医学杂志》9月1日在线版上(N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJM1308075])。


Gilles Montalescot医生

该试验的受试者均为成年人，平均年龄为63岁，均患有NSTE-ACS且肌钙蛋白呈阳性，入组时间为2009年12月~2012年11月。所有受试者均计划在随机分组后2~48 h内接受冠脉造影。被随机分至预治疗组的患者在血管造影前接受了30 mg负荷剂量的普拉格雷，在实施PCI时再追加30 mg。被随机分至对照组的患者在血管造影前接受安慰剂，在实施PCI时接受60 mg普拉格雷。

在一项涉及23例患者的药效动力学亚研究中，研究者发现：“在建立动脉通路时(中位时间为首次给予负荷剂量后4.8 h)，预治疗组的血小板抑制水平高于对照组，这可能是预治疗组出血并发症发生率更高的原因之一。”

值得注意的是，在所有预设的亚组中[包括诸如老年、糖尿病、全球急性冠脉事件注册(GRACE)风险评分≥140等高危人群]，普拉格雷均未显示出对抗缺血事件的保护作用。

“上述结果提示，比氯吡咯雷更强的抗血小板治疗并不能预防导管插入前或PCI后发生心肌梗死。”在缺少P2Y12抑制的对照组中，接受CABG或药物治疗的患者并未出现额外的缺血事件。事实上，其他研究已显示，由于从入院至导管插入的间隔时间很短，缺血事件的风险“极低”。

对使用阿司匹林的NSTE-ACS患者加用氯吡咯雷的益处已在CURE(不稳定型心绞痛患者使用氯吡咯雷预防复发事件)研究中得到了证实。在该研究中，一个较小亚组的患者在PCI前使用了该药，结果显示缺血事件显著减少，从而开了导管插入前给予氯吡咯雷治疗的先河，尽管随后的研究并不支持这一发现。对NSTE-ACS患者给予氯吡咯雷、阿司匹林预治疗以减少侵入性操作后的缺血事件，已经是临床上司空见惯的做法，而且被美国心脏病学会基金会/美国心脏协会(ACCF/AHA)指南列入了Ⅰ类建议，这种做法也被扩展用于普拉格雷等新型口服P2Y12拮抗剂。然而这一做法并未得到有力的研究证据支持。

然而，普拉格雷比氯吡咯雷作用更强、起效更快。研究者总结道：“我们的结果支持在已知冠脉解剖并且已确定以PCI为治疗策略的情况下使用普拉格雷。”

这项研究获得了第一三共和礼来的支持。包括Montalescot医生在内的多名作者报告称存在利益冲突。

随刊述评：新发现或有助NSTEMI治疗趋于合理

John F. Keaney Jr.医生在随刊述评中指出，现行指南建议采用阿司匹林和一种P2Y12抑制剂对接受PCI的NSTE心肌梗死患者进行双联抗血小板治疗，以抑制血小板活化从而预防复发缺血，而且普拉格雷便在可作为阿司匹林补充的药物之列(N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJMe1308820])。

普拉格雷已被证实在这种情况下使用是有效的，但是“我们对于双联抗血小板药物的理解仍不充分”。

在这项研究中，Montalescot医生及其同事为我们带来了有关普拉格雷用药时机的新见解，其研究结果强调了一代和二代P2Y12抑制剂之间的差异，换言之，普拉格雷“代谢更高效，产生的血小板抑制作用更快、更完全”。

这一发现有可能使NSTEMI患者的院内治疗更加合理，Keaney Jr.医生解释道，正如本项研究告诉我们的，将普拉格雷留到血管造影后再用，将使我们得以将该药仅用于将要接受PCI 的患者。这样做反过来又有助于避免需接受CABG的NSTEMI患者因按照现行指南在入院后很快使用P2Y12拮抗剂而推迟CABG(在P2Y12拮抗剂治疗后需等待5~7天才能实施手术，以减少出血风险)。

Keaney医生是《新英格兰医学杂志》副主编，他报告称无其他利益冲突。他也是马萨诸塞大学的内科学教授、Umass纪念医疗中心心血管内科主任。

By: SHARON WORCESTER, Cardiology News Digital Network

Pretreatment with the P2Y12 antagonist prasugrel in patients with non-ST–segment elevation acute coronary syndromes did not reduce the rate of major ischemic events, but did increase the rate of major bleeding complications within 30 days of coronary angiography in the randomized, controlled, phase III ACCOAST trial.

The incidence of the primary efficacy endpoint – a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7 – was similar in 2,037 patients who were randomized to receive prasugrel before and after angiography, and in 1,996 patients who were randomized to receive treatment only after angiography (10.0% and 9.8%; respectively; hazard ratio, 1.02), Dr. Gilles Montalescot of Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, and colleagues found.

The findings were similar, with no significant differences noted between the pretreatment and control groups with respect to the primary efficacy endpoint, among the 2,770 patients managed by percutaneous coronary intervention (PCI), compared with the entire cohort ultimately managed by PCI, coronary artery bypass grafting (CABG), or medical treatment alone.

However, the rate of a key safety endpoint – thrombolysis in myocardial infarction (TIMI) major bleeding episodes through day 7 – was increased in those in the pretreatment group, compared with the control group (2.6% vs. 1.4%; hazard ratio, 1.90), the investigators said, noting that the findings, which were reported at the annual congress of the European Society of Cardiology and simultaneously published online Sept. 1 in the New England Journal of Medicine, were confirmed at 30 days.

"There was an increase by a factor of 3 in all major bleeding not related to CABG and an increase by a factor of 6 in life-threatening bleeding not related to CABG. TIMI minor bleeding events were also increased with pretreatment compared with no pretreatment (hazard ratio, 2.50)," they wrote (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJM1308075]).

Patients in the trial were adults with a mean age of 63 years who had non-ST–segment elevation (NSTE) acute coronary syndromes and a positive troponin level. They were enrolled between Dec. 6, 2009, and Nov. 16, 2012. All were scheduled to undergo coronary angiography within 2-48 hours following randomization.

Those randomized to the pretreatment group received a 30-mg loading dose with prasugrel before angiography, and an additional 30 mg at the time of PCI. Those randomized to the control group received a placebo before the angiography, and 60 mg of prasugrel at the time of PCI.

In a pharmacodynamic substudy involving 23 patients, the investigators noted that "at the time of arterial access, a median of 4.8 hours after the first loading dose, there was greater platelet inhibition in the pretreatment group than in the control group, which may have contributed to the increased rate of bleeding complications in the pretreatment group."

Of note, the lack of protection afforded by prasugrel against ischemic events was demonstrated consistently across all prespecified subgroups, including high-risk groups such as the elderly, those with diabetes, and those with a Global Registry of Acute Coronary Events (GRACE) risk score of 140 or higher.

"This suggests that stronger [than clopidogrel] antiplatelet therapy does not prevent the occurrence of a myocardial infarction before catheterization or after PCI," the investigators wrote. Nonetheless, the lack of P2Y12 inhibition in the control group did not result in an excess of ischemic events in patients who underwent CABG or medical therapy. In fact, other studies have shown that currently, the risk of ischemic events is "extremely low" because of the short time between admission to the hospital and catheterization.

The benefit of adding clopidogrel to aspirin in patients with NSTE acute coronary syndromes was demonstrated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, in which a small subgroup of patients received the drug prior to undergoing PCI; the significant reduction in ischemic events set a precedent for clopidogrel treatment before catheterization, although subsequent studies have not supported the finding. The pretreatment use of clopidogrel and aspirin in patients with NSTE acute coronary syndrome to help reduce ischemic events following an invasive procedure is commonplace, and is included as a class I recommendation in guidelines from the American College of Cardiology Foundation–American Heart Association. This is despite a lack of rigorous studies supporting the practice, which has often been extended to new oral P2Y12 antagonists like prasugrel as well, they explained.

However, prasugrel is more potent and has a more rapid onset of action than clopidogrel. "Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy," they concluded.

This study was supported by Daiichi Sankyo and Eli Lilly. Multiple study authors, including Dr. Montalescot, reported having disclosures.

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Findings may streamline NSTEMI care

Current guidelines recommend dual antiplatelet therapy with aspirin and a P2Y12 inhibitor to inhibit platelet activation and thereby prevent recurrent ischemia in patients with NSTE myocardial infarction who are undergoing PCI, and prasugrel is among the agents available to complement aspirin.

Prasugrel is known to be effective in this setting, but "our knowledge about the administration of dual antiplatelet therapy remains incomplete," Dr. John F. Keaney Jr. wrote in an editorial. He noted that the timing for starting P2Y12 inhibition has been unclear.

In this study, Dr. Montalescot and colleagues offer new insight into the timing of prasugrel administration, and the findings highlight the difference between first- and second-generation P2Y12 inhibitors – namely, prasugrel "undergoes more efficient metabolism, producing faster and more complete platelet inhibition," he said.

The findings may streamline care in patients with NSTEMI in the hospital, he said, explaining that reserving prasugrel administration until after angiography, as indicated in this study, allows it to be limited to patients who will undergo PCI. This, in turn, will prevent the delays in treatment common among NSTEMI patients undergoing CABG who have received P2Y12 antagonist treatment soon after hospital admission per current guidelines, and who must wait 5-7 days after P2Y12 antagonist treatment before the procedure can be performed, due to the risk of excess bleeding.

Dr. Keaney is an associate editor for the New England Journal of Medicine. He reported having no other disclosures. Dr. Keaney is professor of medicine at the University of Massachusetts, and chief of the division of cardiovascular medicine at UMass Memorial Medical Center, both in Worcester. Dr. Keaney’s editorial was published with the article by Dr. Montalescot and his associates (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJMe1308820]).