院前使用比伐卢定可减少PCI出血

旧金山——一项纳入2,218例患者的随机对照试验显示，对尚未接受经皮冠状动脉介入(PCI)治疗的ST段抬高性心肌梗死患者在救护车上给予比伐卢定，与给予普通或低分子量肝素和可选的糖蛋白Ⅱb /Ⅲa抑制剂相比，可显著改善30天出血结局。

巴黎狄德罗大学Bichat医院冠脉治疗单元主任Philippe Gabriel Steg医生及其同事在经导管心血管治疗(TCT)年会上报告，与对照组相比，比伐卢定组的主要结局(死亡或与冠状动脉旁路移植术[CABG]无关的大出血的复合终点)减少了近40%。比伐卢定组和对照组的30天主要结局发生率分别为5.1%和8.4%。

然而，在EUROMAX(欧洲救护车急性冠状动脉综合征血管造影)试验中，比伐卢定组的30天急性支架内血栓形成率约为对照组的6倍(1.1% vs. 0.2%)。但这并没有转化为心肌梗死风险增加。比伐卢定组的心肌梗死发生率与对照组相似(1.7% vs. 0.9%)。

次要终点(30天死亡、再梗死或非CABG大出血的复合终点)发生率也显著降低，比伐卢定组和对照组分别为6.7%和9.1%。

这项研究同期发表在《新英格兰医学杂志》10月30日在线版上(N. Engl. J. Med. 2013 Oct. 30 [doi: 10.1056/NEJMoa1311096])。

比伐卢定的获益主要来自出血的减少，而不是死亡率的下降。比伐卢定组与CABG无关的大出血风险为2.7%，对照组为6.1%，即前者的风险相对下降57%。


Philippe Gabriel Steg医生

30天心源性或非心源性死亡率在两组之间无显著差异，比伐卢定组和对照组的心源性死亡率分别为2.4%和3%，非心源性死亡率分别为0.5%和0.1%。

这项研究的效能不足以评估死亡率。Steg医生在接受采访时表示，希望通过分析来自EUROMAX和既往一项显示PCI前给予比伐卢定有可行性的重要试验——HORIZONS-AMI(采用血管重建术和支架术协调急性心肌梗死的结局)试验——的组合数据评估1年时死亡风险。

Steg医生及其同事开展EUROMAX研究旨在观察，在院前治疗和糖蛋白Ⅱb /Ⅲa抑制剂、血小板P2Y12受体抑制剂和PCI桡动脉入路用法演变的当前临床实践中，这些获益是否仍然存在。

EUROMAX研究的结果在各个患者亚组中均一致，包括根据PCI入路或P2Y12抑制剂选择界定的亚组。

Steg医生认为这一发现将改变临床实践，使欧洲的急救人员更倾向于选用比伐卢定。在欧洲，通常在救护车转运途中就开始抗凝治疗，这一做法在美国尚未被广泛采纳。

HORIZONS-AMI试验的主要研究者、哥伦比亚大学心血管研究与教育系主任Gregg W. Stone博士在本次会议上担任了EUROMAX研究的评论员，他将这两项研究的结果汇总，进行了初步的meta分析。初步结果提示，比伐卢定在30天大出血、输血、血小板减少、死亡和亚急性支架内血栓形成的发生率方面具有显著获益，但急性支架内血栓形成的风险大约增加了5倍。Stone博士认为，有必要开展研究以确定坎格雷洛抗血小板治疗能否解决急性血栓形成风险增加的问题。

Steg医生从Medicines公司获得了酬金，该公司资助了本项研究并且销售比伐卢定。他还报告称与另外16家公司存在利益关系。Steg医生的4名合作者是Medicines公司的雇员，另有12名合作者报告称与该公司和/或另外多家公司有利益关系。Stone博士报告称与波士顿科学、礼来及其他公司存在利益关系。

专家点评：美国应采纳这一做法


Philippe Généreux医生

罗切斯特梅奥医院内科的Bernard J. Gersh医生在新闻发布会上评论指出，这是一项重要的试验，将改变临床实践。

印第安纳波利斯圣文森特心脏中心的James B. Hermiller医生提醒道，尚不清楚两组在大出血事件方面的明显差异会如何转化为死亡率的不同。

纽约长老会医院的Philippe Généreux医生指出，这一结果对于像加拿大这样幅员辽阔的国家尤其重要。在加拿大，从开始转运到实施PCI往往需要45~60分钟的时间。


James B. Hermiller, Jr.医生

但当被问及如何让美国采纳欧洲常用的院前启动抗凝治疗的做法时，这些专家均没有好的解决办法。Hermiller医生指出：“在现场进行心电图检查就已经不容易了，更不用说给予抗凝药物了，但是我们还是得尽力做到这一点，因为这很重要。” Gersh医生表示：“在多个地区共用一套急救系统的情况下，可以对系统进行调整以采纳这种院前抗凝的做法，但在并存多套急救系统的大城市里，要做到这一点就难得多。”


Bernard J. Gersh医生

Généreux医生报告称与心血管系统公司和雅培血管存在利益关系。Gersh医生报告称与制药产品研发、InspireMD及多家其他公司有利益关系。

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By: SHERRY BOSCHERT, Cardiology News Digital Network

SAN FRANCISCO – Giving bivalirudin in the ambulance to patients with ST-segment elevation MI before primary percutaneous coronary intervention significantly improved 30-day bleeding outcomes in a randomized controlled trial in 2,218 patients, compared with giving unfractionated or low-molecular-weight heparin and optional glycoprotein IIb/IIIa inhibitors.

The bivalirudin group showed nearly a 40% decrease in the primary outcome, a composite of death or major bleeding not associated with coronary artery bypass grafting (CABG), compared with the control group.

Rates for the primary outcome were 5.1% in the bivalirudin group and 8.4% in the control group at 30 days, Dr. Philippe Gabriel Steg and his associates reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

The 30-day rate of acute stent thrombosis, however, was approximately sixfold higher in the bivalirudin group (1.1%) than in the control group (0.2%) in the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial.

That did not translate into an increased risk of infarction, which was similar in the bivalirudin group (1.7%) and the control group (0.9%), Dr. Steg and his colleagues said.

The rates of the main secondary outcome – a composite of death, reinfarction, or non-CABG major bleeding at 30 days – also were significantly lower in the bivalirudin group (6.7%) than in the control group (9.1%), said Dr. Steg, professor of cardiology at Université Paris-Diderot and director of the coronary care unit at Hôpital Bichat, Paris.

The study was published online simultaneously with the presentation (N. Engl. J. Med. 2013 Oct. 30 [doi: 10.1056/NEJMoa1311096]).

The benefit from bivalirudin came mainly from reduced bleeding, not reduced mortality. The risk of major bleeding not associated with CABG was 2.7% in the bivalirudin group and 6.1% in the control group, a significant 57% reduction.

Rates of cardiac or noncardiac death at 30 days did not differ significantly between groups, with cardiac death in 2.4% with bivalirudin and 3% in the control group, and noncardiac death in 0.5% and 0.1%, respectively.

The study was underpowered to assess mortality, Dr. Steg said in an interview. He hopes to assess mortality risk at 1 year by analyzing combined data from EUROMAX and a previous major trial that showed bivalirudin’s utility before percutaneous coronary intervention, the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial (N. Engl. J. Med. 2008;358:2218-30).

Dr. Steg and his associates conducted the EUROMAX study to see if these benefits were still true in the modern era of prehospital treatment and evolving use of glycoprotein IIb/IIIa inhibitors, platelet P2Y12 receptor inhibitors, and radial access for PCI.

The EUROMAX findings were consistent across subgroups of patients, including subgroups defined by PCI access site or by the choice of P2Y12 inhibitor, Dr. Steg reported at the meeting, cosponsored by the American College of Cardiology.

He believes the findings will change practices and convince emergency crews to choose bivalirudin in Europe, where anticoagulation commonly is started in ambulances before arrival at the hospital, a practice that has not yet caught on in most of the United States.

Dr. Gregg W. Stone, primary investigator of the HORIZONS-AMI trial and a discussant of EUROMAX at the meeting, put together a preliminary meta-analysis of the two studies, he reported.

Preliminary results suggest significant benefits from bivalirudin in 30-day rates of major bleeding, transfusion, thrombocytopenia, mortality, and subacute stent thrombosis, with a roughly fivefold increase in the risk of acute stent thrombosis.

Studies are warranted to determine whether antiplatelet therapy with cangrelor might be a solution to the acute thrombosis risk, said Dr. Stone, professor of medicine and director of cardiovascular research and education at Columbia University, New York.

Dr. Steg received fees from The Medicines Company, which sponsored the study and markets bivalirudin, and he reported financial associations with 16 other companies.

Four of his colleagues in the study were employees of The Medicines Company, and 12 other colleagues reported financial associations with that company and/or multiple other companies. Dr. Stone reported financial associations with Boston Scientific, Eli Lilly, and other companies.

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The U.S. needs to adopt this

This is an important trial that will change clinical practice, Dr. Bernard J. Gersh said in a panel discussion at a press briefing.

Dr. James B. Hermiller Jr. cautioned that it remains to be seen how the large difference between groups in major bleeding events translates into mortality over time.

Dr. Philippe Généreux said the results especially are important for a vast country like Canada, where transport to PCI often takes 45-60 minutes.

Asked what changes could get the United States to adopt prehospital initiation of anticoagulation, as is common in Europe, none of the panelists had a solution.

"We have a different competitive system" in Canada, said Dr. Généreux of New York–Presbyterian Hospital and HôpitalSacré Coeur, Montreal. "I’ve never seen anything that suggests that prehospital administration and diagnosis are not beneficial, but how we are going to achieve that in the United States, I don’t know."

"It’s difficult to just get ECGs in the field, let alone administer anticoagulants, but we need to get there because this is very important," said Dr. Hermiller of St. Vincent Heart Center of Indiana, Indianapolis.

Dr. Gersh, professor of medicine at the Mayo Clinic, Rochester, Minn., said that it’s possible to change systemic practices in a regional system such as his that spans rural areas, but it’s much more difficult in big cities with multiple competing medical systems.

"I think there are real benefits to a national health care system as opposed to pure and simple competition. With a national or even a regional health care system, you can develop protocols and mandate them.

This is what’s happened in many countries in Europe," he said. "Our current system, where you may have a city of a million people and four hospitals competing and four different ambulance systems, is not conducive to this. Unless people are prepared to sit down and say, ‘We’ll share the burden,’ I don’t have any idea" how the U.S. system will change.

Dr. Généreux reported financial associations with Cardiovascular Systems Inc. and Abbott Vascular. Dr. Gersh reported financial associations with Pharmaceutical Product Development, InspireMD, and multiple other companies.