PPI VS 氯吡格雷 ——当常规遇上指南

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百家争鸣之消化界
各种PPI药物对CYP2C19的反应不同,奥美拉唑对氯吡格雷的减效作用
并不能代表所有PPI;
需要大规模临床试验进一步探讨不同PPI对氯吡格雷药动学和药效学的
影响。另外,PPI与氯吡格雷之间的相互作用是否的确产生不良转归尚 须进一步评价,药理学上明显的药物间相互作用,不一定就会在临床 上产生影响;
而发生药物相互作用,其程度取决于与CYP450同工酶相对亲合力的大
小,高亲和力化合物将与酶结合并抑制低亲和力化合物的生物转化。
PPI与氯吡格雷的药代学影响
Ki值越小表示对该同工酶抑制效力越强
PPI与氯吡格雷的药代学影响
对CYP2C19的抑制强度:兰索拉唑>奥美拉唑>埃索美拉唑>泮托拉唑>雷贝拉唑
最新资料
最新资料

Thromb Haemost. 2009 Apr;101(4):714-9. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Patients receiving dual antiplatelet treatment with aspirin and clopidogrel are commonly treated with proton pump inhibitors (PPIs). Attenuating effects on platelet response to clopidogrel have been reported solely for the PPI omeprazole. PPIs differ in their metabolisation properties as well as their potential for drug-drug interactions. The aim of this study was to investigate the impact of different PPIs (pantoprazole, omeprazole, esomeprazole) on platelet response to clopidogrel in patients with previous coronary stent placement under chronic clopidogrel treatment. In a crosssectional observational study, consecutive patients under clopidogrel maintenance treatment (n = 1,000) scheduled for a control coronary angiography were enrolled. Adenosine diphosphate (ADP)induced platelet aggregation (in AU*min) was measured with multiple electrode platelet aggregometry (MEA). From the entire study population, 268 (26.8%) patients were under PPI treatment at the time point of platelet function testing (pantoprazole, n = 162; omeprazole, n = 64; esomeprazole, n = 42). Platelet aggregation (median [interquartile range]) was significantly higher in patients with omeprazole treatment (295.5 [193.5-571.2] AU*min) compared to patients without PPI treatment (220.0 [143.8-388.8] AU*min; p = 0.001). Platelet aggregation was similar in patients with pantoprazole (226.0 [150.0-401.5] AU*min) or esomeprazole (209.0 [134.8-384.8] AU*min) treatment compared to patients without PPI treatment (p = 0.69 and p = 0.88, respectively). Attenuating effects of concomitant PPI treatment on platelet response to clopidogrel were restricted to the use of omeprazole. No attenuating effects on platelet response to clopidogrel were observed for pantoprazole or esomeprazole. Specifically designed and randomized clinical studies are needed to define the impact of concomitant PPI treatment on adverse events after percutaneous coronary intervention.
矛盾焦点
抗血小板治疗相关消化道出血现状如何? 近期发表的两项研究对临床影响如何?如何评价? 所有PPI会影响氯吡格雷的效果嘛? 如何预防抗血小板药物引起的消化道出血? 患者发生消化道出血时,如何处理?
PPI—药理作用
众矢之的——CYP2C19
PPI与氯吡格雷的药代学影响
氯吡格雷通过细胞色素P450(CYP)同工酶CYP 3A4和2C19等的代谢,
PCI术后患者接受阿司匹林和氯吡格雷抗血小板治疗的同时,为预防其
胃肠道不良反应,选用PPI中的雷贝拉唑较为合适。如果选用H2受体 拮抗剂,则须剂量加倍;
百家争鸣之药学界

PPI与氯吡格雷的相互作用主要通过CYP2C19同工酶;
各种PPI与氯吡格雷的相互作用程度有别; 基因多态性影响氯吡格雷代谢:白人约30%,黑人约40%,东亚人约55%; 对于接受氯吡格雷治疗且同时需要抑酸干预的患者,使用PPI治疗时,应尽可能选择对
百家争鸣之心血管
2009年4月发表于《血栓与止血学》杂志上的一项研究表明,仅奥美拉唑会减
弱氯吡格雷的抗血小板作用,而泮托拉唑和埃索美拉唑不会增加再发心梗风 险,相对安全有效 另一项研究也证实,泮托拉唑不会升高急性心梗患者的再 梗死率。因此,基于当前证据,不推荐ACS患者联用氯吡格雷与奥美拉唑;
J Med. 2005 Jan 20;352(3):238-44.
2008年美国心脏病学会基金会(ACCF)/美国胃肠病学会(ACG)/AHA联合公布
的专家共识对氯吡格雷替代阿司匹林提出质疑,建议有消化道溃疡复发风险者
采用阿司匹林联合PPI治疗,另外,急性心梗后服用阿司匹林的患者同时加用质
子泵抑制剂(PPI)。
率为2.47%,较对照组明显增高,且与阿司匹林的剂量呈正相关。服用
氯吡格雷75 mg患者的胃肠道出血住院率为0.7%。当每日 75~325 mg
的阿司匹林与氯吡格雷合用时,与单独使用上述剂量的阿司匹林相比,
大出血风险明显增加(P<0.001);
氯吡格雷与阿司匹林出血风险相当 双抗患者有出血高危因素的,常规使用PPI预防出血;

OBJECTIVE: To evaluate the interaction between clopidogrel and proton pump inhibitors (PPIs). DATA SOURCES: Literature retrieval was accessed through PubMed (1980- January 2009), abstracts from 2008 American Heart Association and 2009 Society of Cardiovascular Angiography and Interventions Scientific Sessions, and media press releases using the terms clopidogrel, proton pump inhibitors, cytochrome 2C19, genetic cytochrome P450 polymorphisms, and drug interaction. In addition, reference citations from publications identified in the search were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant original research articles and review articles were evaluated. Articles were selected if they were published in English and focused on any of the key words or appeared to have substantial content addressing the drug interaction. DATA SYNTHESIS: Recent attention has been placed on a potential interaction observed between clopidogrel and the widely used PPIs. Preliminary evidence suggests that omeprazole interacts with clopidogrel, reducing clopidogrel's antiplatelet effects as measured by various laboratory tests. Most data indicate that the interaction involves the competitive inhibition of the CYP2C19 isoenzyme. The interaction appears to be clinically significant, as several retrospective analyses have shown an increase in adverse cardiovascular outcomes when PPIs and clopidogrel are used concomitantly. However, this may not be a class effect. CONCLUSIONS: Available data suggest that omeprazole is the PPI most likely to have a significant interaction with clopidogrel. Further studies are needed to determine that an interaction between the other PPIs and clopidogrel does not exist. In situations in which both clopidogrel and a PPI are indicated, pantoprazole should be used since it is the PPI least likely to interact with clopidogrel.
双抗治疗支持PPI使用证据
双抗治疗支持PPI使用证据
双抗治疗不支持PPI使用证据
双抗治疗不支持PPI使用证据
思考
PPI真的死刑?
PPI究竟怎么用?
不能使用PPI,心内科医生还能做什么?
心血管、消化科、临床药学三方讨论
百家争鸣之消化界
为了预防长期服用NSAIDs引起的胃肠道不良反应,首选PPI是消化界共
5种PPI的药代动力学和药物间相互作用比较(Drug Safety 2006,29:769-784)
冠心病患者使用PPI的证据
消化道出血率高
全球急性冠脉综合征注册研究(GRACE)显示:ACS患者合并大出血的发生率为
2.3%~4.8%,最常见的出血部位为消化道,占所有出血部位的31.5%。也有回顾性
研究表明,ACS患者合并严重胃肠道出血的发生率为3%。
消化道出血死亡率高
ACS合并胃肠道出血的患者预后差,死亡率高达36.3%,与未合并胃肠道出血
的ACS患者相比具有显著差异。
出血的高危因素
既往有上消化道出血病史、活动性消化性溃疡、既往有消化性溃疡史(特别是具
有溃疡并发症者)、已知的胃息肉和恶性肿瘤等。
氧化水解形成具有药理活性的硫醇衍生物,该活性代谢产物不可逆地 与血小板二磷酸腺苷受体P2Y12结合,最终抑制纤维蛋白原受体
GPⅡb/Ⅲa活化,从而抑制血小板聚集。
PPI也主要通过CYP2C19和CYP3A4同工酶在肝脏代谢。 PPI与氯吡格雷合用时可能会因共同竞争CYP450同工酶的相同结合位点
最新资料

Ann Pharmacother. 2009 May 26. [Epub ahead of print] Links Drug-Drug Interaction Between Clopidogrel and the Proton Pump Inhibitors (July/August)(CE). Norgard NB, Mathews KD, Wall GC. School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY.
氯吡格雷与阿司匹林的消化道损害机制不同 如果氯吡格雷不能与PPI联用,心血管医生将无所适从 H2受体阻滞剂能否取代PPI安全有效地防治抗血小板药物相关消化道出血还有
待证实;
氯吡格雷与PPI相互作用并无定论 发表于JAMA的研究有一定局限性:回顾性研究;未考虑CYP多态性;该研究
Fra Baidu bibliotek
未进行分层分析,如所纳入人群的生活方式(吸烟、饮酒等)资料不详。
识;
权衡抗血小板治疗降低“心血管缺血风险”和 增加“消化道出血风险”
的利弊以及应用PPI有利止血和其减弱氯吡格雷作用之利弊应侧重考虑
心血管缺血风险;
PPI预防性用药需有针对性:消化性溃疡病史无出血但有幽门螺杆菌感
染;近年有消化道溃疡出血病史;需双重抗血小板制剂。超过下列一项 因素者:年龄≥60岁、应用皮质激素超过6日或更长时间、脓毒症患者, 也应考虑应用PPI。一般疗程不超过8周;
PPI 相关指南与共识
2007年美国心脏病学会/美国心脏学会(ACC / AHA)发表指南指出,既往有消
化道出血病史者,在单独或联用阿司匹林和氯吡格雷时,可加用质子泵抑制剂 (PPI)以降低再出血风险;
Aspirin plus PPI safer than clopidogrel if there is history of GI bleeding. N Engl
CYP2C19抑制效力小的泮托拉唑,从而最大程度地减少药物不良反应和心血管不良事件
的发生;
氯吡格雷与PPI的多代谢途径,不能简单禁止氯吡格雷与PPI联用; 药理理论研究不能完全代替临床试验,还是需要大规模临床试验结果。
百家争鸣之心血管
目前大部分ACS患者会接受阿司匹林联合氯吡格雷抗血小板治疗; 德里(Derry)等的研究表明,长期使用阿司匹林致消化道出血的发生
暨南大学第三附属医院 珠海市人民医院心内科 石理
冤家对头—东窗事发
为了降低抗血小板治疗患者的消化道出血风险,加用质子
泵抑制剂(PPI)似乎已成为临床常规,但今年初《加拿大 医学会杂志》[CMAJ 2009,180(7):713]和《美国医学会杂 志》[JAMA 2009,301(9):937]发表的两项大规模回顾性研 究对这一用法提出了质疑。两项研究均显示,氯吡格雷与 PPI联用增加心血管事件发生风险。此后美国FDA也发出警 告,提醒医生警惕以上两药联用的风险。
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