肝素与比伐卢定在NSTEMI患者中具可比性

巴黎——欧洲经皮冠状动脉介入治疗学会(EAPCI)2013年会上公布的一项瑞典全国注册研究的分析结果显示，在进行经皮冠状动脉介入(PCI)治疗的非ST段抬高型急性冠状动脉综合征(NSTE-ACS)患者中，接受肝素治疗的患者的生存率与接受比伐卢定治疗的患者相似。

Oskar Angeras博士

最近的2011年美国心脏病学学院和美国心脏协会指南推荐将比伐卢定作为PCI期间的首选抗凝剂(J. Am. Coll. Cardiol. 2011;58:e44-e122)，而欧洲心脏病学会的最新NTSE-ACS患者管理指南推荐将fondaparinux(Arixtra)作为首选抗凝剂，其次为地位平等的比伐卢定、普通肝素和低分子量肝素(Eur. Heart J. 2011;32:2999-305zz4)。比伐卢定在这些指南中的推荐位次主要基于急性插管和紧急介入治疗分类策略(ACUITY)研究结果(N. Engl. J. Med. 2006;355:2203-16)，但该研究对目前临床实践的指导意义已不如以前，因为目前的临床实践已发生一些改变。

为了评估近期临床实践中肝素和比伐卢定对患者生存的影响，瑞典哥德堡萨赫尔格雷斯卡大学医院的心脏介入医生Oskar Angeras博士及其同事进行了此项分析，分析对象是参与瑞典冠状动脉造影和血管成形术注册(SCAAR)研究的28个瑞典中心2006~2011年间连续收治的41,537例在未使用糖蛋白Ⅱb/Ⅲa抑制剂情况下接受PCI治疗的NSTE-ACS患者。患者的平均年龄为68岁，约75%为生物标志物阳性，约47%采用桡动脉入路进行PCI。约27,000例患者接受普通肝素或低分子量肝素治疗，约8,700例接受比伐卢定治疗。约6,000例患者的抗凝剂应用数据未能获取。

结果显示，在已知接受抗凝治疗的约35,000例患者中，比伐卢定亚组的30天死亡率比肝素组显著增高50%。校正已知和未知混杂因素后发现，肝素亚组和比伐卢定亚组的死亡率相似。研究者在使用不同抗凝剂的患者中，年龄、性别、PCI入路部位不同的患者中，以及有或无糖尿病的患者中，均观察到相似死亡率。研究数据还显示，肝素亚组和比伐卢定亚组的出血发生率无显著差异，但Angerås博士表示分析涵盖的所有年份的出血资料均未能获取。

Angeras博士表示需谨慎解读分析得出的结论，后者有待随机对照研究的证实。他们计划近期开展一项纳入约6,000例瑞典患者的随机对照研究，对肝素和比伐卢定进行比较，这将有望解决二者在接受PCI的NSTE-ACS患者中孰优孰劣的问题。此外，Angerås博士在进行此项分析之前较常使用比伐卢定作为抗凝剂，此分析结果促使其在临床实践中更常规地使用肝素，而由此为患者省下的钱使他们能够更自由地使用药物洗脱冠状动脉支架，目前药物洗脱支架在其患者中的应用率已从30%增至80%。Angeras博士承认出血是不良的并发症，但同时表示如果出血不导致死亡率增加的话，这一替代终点的临床意义不大，而且上述分析显示比伐卢定亚组和肝素亚组的出血率基本相同。

Angeras博士声明无经济利益冲突。

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By: MITCHEL L. ZOLER, Cardiology News Digital Network

PARIS – Heparin treatment may produce survival rates as does treatment with bivalirudin in patients with non–ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention, based on analysis of data from more than 40,000 patients collected in a nationwide Swedish registry.

The new finding “questions the superiority of bivalirudin over heparin in the absence of glycoprotein IIb/IIIa blockade” in these patients and produced some doubt about the need for the extra expense of using bivalirudin (Angiomax) to treat these patients, Dr. Oskar Angerås said at the annual meeting of the European Association of Percutaneous Coronary Interventions. The finding prompted him recently to shift his practice and treat non–ST-elevation acute coronary syndrome (NSTE-ACS) with heparin rather than bivalirudin when performing percutaneous coronary intervention (PCI), he said in an interview. It also led him and his associates to plan to soon start a randomized, controlled trial to compare the two treatment options in about 6,000 Swedish patients, a study he hopes will definitely address this issue.
 
Bivalirudin was the highest-rated anticoagulant for use during PCI in the most recent, 2011 guidelines of American College of Cardiology and American Heart Association (J. Am. Coll. Cardiol. 2011;58:e44-e122), while the European Society of Cardiology’s most recent guidelines on managing patients with NTSE-ACS rated fondaparinux (Arixtra) as the top anticoagulant and put bivalirudin, unfractionated heparin, and low-molecular-weight heparin on equal footing a step below fondaparinux (Eur. Heart J. 2011;32:2999-305zz4).

The role of bivalirudin in this setting largely stems from results of the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial (N. Engl. J. Med. 2006;355:2203-16), but the trial has reduced relevance today because of several changes in practice since then, said Dr. Angerås , an interventional cardiologist at Sahlgrenska University Hospital in Gothenburg, Sweden. In ACUITY, all patients received a glycoprotein IIb/IIIa inhibitor, a drug class now infrequently used in these patients. Fewer than 60% of ACUITY patients underwent PCI, fewer than 60% were biomarker positive, and among those who did receive a coronary stent only 6% had their intervention done via radial-artery access, “quite different from our daily practice” today, he said.

Two other published studies also compared bivalirudin and heparin, the Hirulog Angioplasty Study (N. Engl. J. Med. 1995;333:764-9), and the Intracoronary Stenting and Antithrombosis Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial (N. Engl. J. Med. 2008;359:688-96), but both of those studies only found a difference in bleeding complications in favor of bivalirudin, but no mortality difference between the drugs, he noted.

To assess the impact of the two alternatives on patient survival in more contemporary practice, Dr. Angerås and his associates 41,537 consecutive NSTE-ACS patients who underwent PCI without use of a glycoprotein IIb/IIIa inhibitor at any of the 28 Swedish centers that participate in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) during 2006-2011. The patients averaged about 68 years of age, about 75% were biomarker positive, and about 47% underwent PCI using a radial-artery approach. Nearly 27,000 of these patients received heparin, either in the unfractionated or low-molecular weight form, and about 8,700 received bivalirudin. Data on anticoagulant use were not available for about 6,000 patients.

Among the roughly 35,000 patients with known anticoagulant treatment, those who received bivalirudin had a statistically significant 50% increased 30-day mortality rate, compared with those who receive heparin. After the researchers did a series of statistical adjustments to control for both known and unknown confounders, the mortality rates in the heparin and bivalirudin subgroups became roughly similar, without a statistically significant difference, Dr. Angerås reported. The researchers saw similar mortality rates, regardless of the anticoagulant used; the patient’s age, sex, PCI access site; or the presence or absence of diabetes. The registry data also showed no statistically significant difference in bleeding episodes between the heparin- and bivalirudin-treated patients, but Dr. Angerås said that information on bleeding was not available for all of the years included in the analysis.

Patients who receive heparin and bivalirudin “are two different groups,” commented Dr. Andreas Baumbach, an interventional cardiologist at the Bristol (England) Heart Institute and designated discussant for the study. “It’s no surprise to me that in the group that I would consider to have higher risk,” the patients who received bivalirudin “had more endpoints. When you do all the statistical analysis and make the two groups equal by risk, then you see no difference.”

Dr. Angerås agreed. “We are very cautious about our conclusion,” and he stressed that the issue will not be clearly settled until results from the randomized, controlled study are available.

He also said that he found the result surprising, especially because until recently bivalirudin had been his anticoagulant of choice. Now that he has switched to more routinely using heparin, he has channeled the money he saves on each case into more liberal use of drug-eluting coronary stents in these patients. “Our drug-eluting stent use has risen from about 30% of patients to about 80%,” Dr. Angerås said in an interview. He also acknowledged that bleeding is not a benign complication, but added that bleeding is a surrogate endpoint with less clinical importance if it doesn’t produce increased mortality, and that in the data he reported bleeding rates were roughly equal between the bivalirudin and heparin subgroups.

Dr. Angerås said that he had no disclosures. Dr. Baumbach said that he has received research support from the Medicines Company, which markets bivalirudin (Angiomax).