A retrospective study involving 13,809 patients found no evidence that proton pump inhibitors interfere with the antiplatelet drugs clopidogrel and prasugrel in patients with acute cardiac syndrome. Existing guidelines, which endorse the content use of proton pump inhibitors with antiplatelet drugs in these patients, will therefore not need to be changed.

The results contrast with other recent studies suggesting that proton pump inhibitors (PPIs), especially omeprazole, might diminish the drugs’ antiplatelet effects and clinical efficacy. The study, published online Sept. 1 in the Lancet, was presented concurrently by Dr. Michelle L O’Donoghue at the annual congress of the European Society of Cardiology in Barcelona.

Clopidogrel and prasugrel are in a class of drugs called thienopyridines. They are pro-drugs that are converted by the cytochrome P450 enzyme system into their active metabolites. It was thought that PPIs might interfere with this through their inhibition of a cytochrome P450 isozyme in the liver called 2C19. As a result of these concerns, and of earlier studies that seem to suggest problems, the U.S. Food and Drug Administration and the European Medicines Agency (EMEA) issued safety warnings discouraging the use of PPIs with clopidogrel unless absolutely necessary.

The new study involved a retrospective analysis of one large trial involving 13,608 patients and one small trial involving 201 patients. Both were randomized, controlled trials intended to compare clopidogrel with prasugrel in patients undergoing elective percutaneous coronary intervention. In both trials, the use of a PPI was at the discretion of the treating physician. At the time of randomization, 26% of patients in the smaller trial and 33% of patients in the larger trial were taking PPIs.

The investigators, led by Dr. O’Donoghue of Brigham and Women’s Hospital, Boston, adjusted their results for 28 potential confounders, including age; sex; ethnic origin; history of hypertension, hypercholesterolemia, heart failure, peptic ulcer disease, carotid or vertebral artery disease, or diabetes; previous MI; previous coronary artery bypass graft surgery (CABG); family history; and the use of a drug-eluting stents (Lancet 2009 Sept. 1 [doi:10.1016/S0140-6736(09)61525-7]).

While the investigators did find that PPIs were associated with a reduction in the antiplatelet effects of clopidogrel and prasugrel, this did not translate into any significant differences in clinical outcome. There were no significant differences in all cause death, cardiovascular death, MI, stent thrombosis, major or minor bleeding in thrombolysis-induced myocardial infarction, or net clinical outcome (a combination of death, MI, stroke, and major non-CABG bleeding).

In an accompanying editorial, Dr. Dirk Sibbing and Dr. Adnan Kastrati of Technische Universität München (Munich), praised the investigators for their comprehensive analysis but raised a number of questions. For example, they suggested that patient compliance with thienopyridines might be worse in real life than in the context of the clinical trials. Dr. Sibbing and Dr. Kastrati concluded that PPIs appear not to interact with clopidogrel or prasugrel in terms of clinical outcomes and that patients with a risk profile similar to that in the trials can be safely treated with PPI (Lancet 2009 Sept. 1 [doi:10.1016/S0140-6736(09)61562-2]).

“However,” they wrote, “caution is needed when prescribing PPIs for selected high-risk patients with an intrinsically reduced response to thienopyridines. ... In all cases, careful monitoring of patients’ compliance with a thienopyridine drugs is mandatory.”

The original trials received grant funding from Eli Lilly and Co. and from Daiichi Sankyo. The investigators conducting the retrospective analysis stated that they received no external sources of funding. Dr. Sibbing acknowledged receiving lecture fees from Dynabyte and fees for advisory board activities from Eli Lilly. Dr. Kastrati acknowledged receiving lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, and Eli Lilly.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

一项纳入13,809例患者的回顾性研究发现，尚无任何证据证明质子泵抑制剂(proton pump inhibitors，PPIs)会影响抗血小板药物氯吡格雷(clopidogrel)和普拉格雷(prasugrel)治疗急性心脏综合征患者的疗效。因此，现有指南中支持在此类患者中可同时使用质子泵抑制剂和抗血小板药物的内容并不需要修改。

 

该研究刊发于9月1日网络版的《柳叶刀》(Lancet)上，同时，Michelle L O’Donoghue博士在巴塞罗那举办的欧洲心脏病学会(European Society of Cardiology)年会上做了相关报告。研究的结论与最近的一些研究相反，这些研究表明：质子泵抑制剂特别是奥美拉唑可减少药物的抗血小板作用以及临床疗效。

 

氯吡格雷和普拉格雷属于噻氯吡啶类(thienopyridines)药物。该前体药物经细胞色素P450酶系统转化为其活性代谢产物形式。据认为，质子泵抑制剂可能会影响细胞色素P450在肝脏的同工酶2C19。鉴于对上述后果的担忧以及早期研究所提出的问题，美国食品药品管理局(FDA)和欧洲药品局(EMEA)发出安全警告称，若非绝对必要，不鼓励同时使用质子泵抑制剂与氯吡格雷。

 

该全新的研究对一项纳入13,608例患者的大型临床试验和一项纳入201例患者的小型临床试验进行了回顾性分析。两者均为随机对照试验，旨在比较普拉格雷和氯吡格雷对择期经皮冠状动脉介入治疗患者的疗效。在这2个试验中，是否使用质子泵抑制剂均由经治医生决定。占小型临床试验患者总数26%以及占大型试验33%的患者随机服用了质子泵抑制剂。

 

波士顿市布莱根妇女医院O’Donoghue博士领导的研究团队对28个潜在的混杂因素进行了校正，其中包括年龄、性别、种族、高血压史、高胆固醇血症、心力衰竭、胃溃疡、颈动脉或椎动脉疾病、糖尿病、陈旧性心肌梗死、既往接受冠状动脉搭桥手术(CABG)、家族史以及应用药物涂层支架等(Lancet 2009 Sept. 1 [doi:10.1016/S0140-6736(09)61525-7])。

 

虽然研究人员的确发现质子泵抑制剂与氯吡格雷和普拉格雷抗血小板疗效下降有关，但这并未转化成任何临床结局上的显著性差异。而且，致死性疾病的发生率亦无显著差异，如心血管死亡、心肌梗死、支架内血栓形成、溶栓治疗轻度或重度出血引起的心肌梗死或净临床预后(复合死亡、心肌梗死、中风以及非冠状动脉搭桥术性重度出血事件的总和) 。

 

德国慕尼黑技术大学Dirk Sibbing博士和Adnan Kastrati博士在所附的编者按中对研究人员全面的分析十分赞赏，但也提出了许多问题。例如，他们指出，患者在实际生活中对噻氯吡啶类药物的依从性可能逊于临床试验中的表现。Sibbing 博士和Kastrati 博士认为，质子泵抑制剂似乎并不会影响氯吡格雷或普拉格雷的临床疗效，倘若患者的风险状况和试验情况相似，则可安全地使用质子泵抑制剂(Lancet 2009 Sept. 1 [doi:10.1016/S0140-6736(09)61562-2])。

 

“不过，”他们写道，“在给噻氯吡啶类药物反应性下降的高风险患者开具质子泵抑制剂处方时须保持谨慎……在任何情况下，都应密切监视患者对噻氯吡啶类药物的依从性。”

 

原始试验接受了来自美国礼来公司和日本三共株式会社的基金资助。研究人员声称该回顾性分析未接受任何外部资金资助。Sibbing 博士承认接受了Dynabyte公司的演讲酬金以及礼来公司的咨询费。Kastrati 博士则承认接受过三共株式会社、百时美施贵宝和礼来公司的演讲酬金。

 

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