不同种类质子泵抑制剂对氯吡格雷抗血小板疗效的影响

氯吡格雷作为一种新型的抗血小板药,已与阿司匹林联合广泛应用于临床,成为冠心病抗血小板药物治疗的基石。双联抗血小板治疗使胃肠道并发症的出现增多,故临床上常规加用质子泵抑制剂,以预防双联抗血小板治疗引发的胃肠道并发症。但国外最新研究发现质子泵抑制剂会影响氯吡格雷的疗效,降低其抗血小板的活性,使临床心血管不良事件发生率增加。     

Impact of concomitant use of proton pump inhibitors on anti-platelet therapy of clopidogrel in patients undergoing percutaneous coronary intervention

Background In clopidogrel-treated patients undergoing percutaneous coronary intervention （PCI）, the effect of concomitant use of PPIs on prognosis remains unclear. Methods From July 2010 to June 2012, 600 patients after implantation of drug-eluting stent （DES） were assigned to 3 groups according to the medical therapy： group 1 （n = 200） received dural antiplatelet therapy （DAPT） alone （aspirine 100 mg daily plus clopidogrel 75 mg daily）, group 2（n = 199） received DAFT plus pantoprazole 20 mg daily while group 3（n = 201） received DAFT plus omeprazole 20 mg daily for 1 year. The primary outcome was major adverse cardiovascular events （MACEs） which compose of death, nonfatal myocardial infarction （MI）, nonfatal stroke, target vessel revascularization （TVR） or stent thrombosis （ST） at 1 year. Platelet reactivity was evaluated for all patients before PCI and 1 year after PCI. Results There was no significant difference in the platelet reactivity among the 3 groups at 1-year follow-up（27.3% versus 29.9% versus 29.3%, respectively, P = 0.339）. Neither was there significant difference in the incidence of 1-year MACEs （13% versus 14.6% versus 12.4%, respectively, P = 0.809）. Conclusions Concomitant use of pantoprazole or omeprazole did not influence platelet reactivity or clinical events in patients receiving DAPT after implantation of DES.     

质子泵抑制剂联用抗血小板药物研究进展

加用氯吡格雷的双联抗血小板治疗目前已成为冠心病的常规治疗,然而临床抗血小板治疗会增加胃肠道出血风险,因此临床上常加用质子泵抑制剂(PPIs)来减少胃肠道不良反应。PPIs和氯吡格雷经相同的肝酶代谢,因此两者联用会产生代谢竞争。近期的研究分别从基础和临床角度对此现象进行分析,但并未得出确切的结论,部分研究支持两类药物合用,认为PPIs并未影响氯吡格雷的抗血小板活性效价,未增加临床事件风险;而另一部分研究则持相反意见,还有研究认为只有部分种类的PPIs会影响其抗血小板活性和增加心血管再发事件风险。因此在两类药物的临床应用上应评估PPIs使用的必要性,对需要加用PPIs者首选药物相互影响较小的PPIs。     

Proton pump inhibitor and clopidogrel interaction: The case for watchful waiting

Clopidogrel is an integral part of the management of several important vascular diseases. However the medium to long term clinical outcomes are poorer for these patients if they experience gastro‐intestinal bleeding, hence patients with risk factors for gastro‐intestinal bleeding are frequently prescribed proton pump inhibitors. Conflicting evidence exists as to the existence of an adverse interaction between clopidogrel and proton pump. This review examines the original studies, which suggested the adverse interaction, the subsequent and most recent studies, the pharmaco‐dynamics of the two drugs and suggests an algorithm for the use of clopidogrel with proton pump inhibitors.     

质子泵抑制剂对冠状动脉介入术后患者氯吡格雷抵抗和再发心血管事件的影响

目的:探讨中国福建地区汉族患者择期经皮冠状动脉介入治疗(PCI)术后,质子泵抑制剂(PPI)对实验室氯吡格雷抵抗(LCR)的影响及与再发心血管事件(CVEs)之间的关系。方法:观察345例择期PCI术患者,收集患者服药前后最大血小板聚集率(MPA)和中位数为7个月随访期间CVEs再发的情况。结果:①氯吡格雷联合胃药组的MPA下降幅度明显低于未联合胃药组(P=0.009);氯吡格雷联合PPI组的MPA下降幅度明显低于未联合PPI组(P<0.01);进一步分析发现,氯吡格雷联合泮托拉唑组的MPA下降幅度明显高于奥美拉唑组和其他PPI组(P=0.004)。②服用胃药组的LCR和再发CVEs发生率明显高于未服用胃药组(38.5%∶23.3%,P=0.019;20.6%∶10.0%,P=0.039);服用PPI组的LCR和再发CVEs发生率明显高于未服用PPI组(48.4%∶27.6%,P<0.01;25.8%∶13.8%,P=0.001);奥美拉唑组的再发CVEs明显高于泮托拉唑组和其他PPI组(P=0.035);并且发现氯吡格雷联合奥美拉唑是PCI术后再发CVEs的独立危险因素(P=0.002,RR=3.486,95%CI=1.595～7.618)。结论:PCI术后服用PPI(尤其是奥美拉唑)时,可能会减弱氯吡格雷的疗效,增加心血管不良事件的风险。     

加强对老年人胃部疾病与胃随龄变化研究

胃黏膜增龄变化的基本表现为胃窦固有层腺体数量减少,胃窦黏膜固有层胶原组织增生,但胃底腺腺体实质比略高于非老年组,壁细胞数量在不同年龄组间差异无统计学意义。由于老年人胃体萎缩性胃炎发生率增加,导致部分老年人胃酸偏低,但老化不是胃酸分泌减少的独立原因,年龄增长并不影响空腹状态下胃内氢离子活性。质子泵抑制剂与氯吡格雷合用是否会降低疗效,是当前关注热点。国内对于80岁以上的109例老龄患者观察,认为质子泵抑制剂不影响服用氯吡格雷患者的临床前景,不足之处是观察的例数偏少,且联用质子泵抑制剂治疗时间较短。对老年人根除幽门螺杆菌感染的组织学变化,结果表明,幽门螺杆菌根除者慢性炎症好转率达87．4％,急性活动性炎症好转率为57．8％,较幽门螺杆菌未根除者炎症好转率明显增加。     

Clopidogrel-drug interactions

Multidrug therapy increases the risk for drug-drug interactions. Clopidogrel, a prodrug, requires hepatic cytochrome P450 (CYP) metabolic activation to produce the active metabolite that inhibits the platelet P2Y?? adenosine diphosphate (ADP) receptor, decreasing platelet activation and aggregation processes. Atorvastatin, omeprazole, and several other drugs have been shown in pharmacodynamic studies to competitively inhibit CYP activation of clopidogrel, reducing clopidogrel responsiveness. Conversely, other agents increase clopidogrel responsiveness by inducing CYP activity. The clinical implications of these pharmacodynamic interactions have raised concern because many of these drugs are coadministered to patients with coronary artery disease. There are multiple challenges in proving that a pharmacodynamic drug-drug interaction is clinically significant. To date, there is no consistent evidence that clopidogrel-drug interactions impact adverse cardiovascular events. Statins and proton pump inhibitors have been shown to decrease adverse clinical event rates and should not be withheld from patients with appropriate indications for therapy because of concern about potential clopidogrel-drug interactions. Clinicians concerned about clopidogrel-drug interactions have the option of prescribing either an alternative platelet P2Y?? receptor inhibitor without known drug interactions, or statin and gastro-protective agents that do not interfere with clopidogrel metabolism.     

抗血小板药物所致消化道损伤及其防护研究进展

抗血小板治疗广泛用于心脑血管疾病的预防,但其同时可引起消化道损伤,甚至消化道出血。临床中的双重抗血小板治疗更进一步增加了这些风险。如何在冠心病患者,尤其是消化道出血高危患者中规范、安全地使用抗血小板药物已成为临床上的一个重要课题。     

Proton pump induced thrombocytopenia: A case report and review of literature

Proton pump inhibitors (PPIs) are not widely recognized as a cause of drug-induced thrombocytopenia. Literature is mainly confined to case reports and has been insufficient to explore the possibility that this adverse event may be attributed to a class effect of PPI therapy. We present a case where platelet counts dropped from 177 (×10³ per mm³) to 47 (×10³ per mm³) within 6 days after the patient was switched from omeprazole to pantoprazole. There have been case reports of thrombocytopenia caused by PPIs; however, this is noted to be extremely rare. In our case, the patient developed thrombocytopenia on two separate occasions of exposure to pantoprazole, which resolved after stopping the medicine, thus providing definite proof of pantoprazole causing thrombocytopenia. Moreover, the patient did not have thrombocytopenia with omeprazole, thus suggesting that thrombocytopenia with PPIs might be an individual drug effect rather than a class effect. This occurrence has been reported in three other case reports as well. From the nine case reports that we have reviewed, direct causal relationship was found in a few reports only. It has been hypothesized that this adverse effect may be immune mediated, but further investigations are still needed to identify the exact pathogenesis.     

Controversy of proton pump inhibitor and clopidogrel interaction: a review

A proton pump inhibitor (PPI) is often co-prescribed with clopidogrel to reduce the gastrointestinal risk of bleeding ulcers in patients following acute coronary syndrome or a stent implant. However, the safety issue of such practice has been scrutinized after some studies reporting an increased incidence of cardiovascular events and mortality, although there have also been contrary research reports. This has lead to a warning statement from the US Food and Drug Administration cautioning the concomitant use of PPI and clopidogrel. This review examines the evidence of PPI as gastroprotective agent, histamine H(2) antagonists as an alternative therapy, the influence of PPI on the antiplatelet effect of clopidogrel, and the controversies of various studies.     

Pantoprazole-induced thrombocytopenia in patients with upper gastrointestinal bleeding

Proton pump inhibitors (PPIs) are highly effective drugs for patients suffering from peptic ulcer and gastro-esophageal reflux diseases, but recent studies have indicated possible risks with the long-term use of PPIs, such as osteoporosis, fractures, increased risk of pneumonia, diarrhea, iron and vitamin B12 deficiencies. There are publications written as a case study that indicate thrombocytopenia as side effects of PPIs, but there is no study on this subject. This study aimed to investigate the development of thrombocytopenia in patients with short-term use of PPI-infusion therapy. In this study, the records of the patients were evaluated retrospectively, for the period between January 2012 and January 2013. Thirty-five patients with upper gastrointestinal bleeding were enrolled. Platelet counts were analyzed before treatment, and on the first, second and third day of treatment, respectively. All patients were treated with intravenous pantoprazole. Hemogram values of patients were analyzed before and after PPI infusion treatment. Platelet counts were found to decrease from the first day to the third day of treatment (249?714.29/µl, 197?314.29/µl, 193?941.18/µl, 183?500/µl, respectively). The platelet count decrease was statistically significant (p?<?0.001). After cessation of infusion therapy, platelet counts began to rise on the fourth day. Three patients had severe thrombocytopenia on the third day of the treatment. (69?000/µl, 97?000/µl and 49?000/µl respectively). Platelet counts recovered after discontinuation of treatment. In conclusion, this study demonstrates that PPIs may cause thrombocytopenia, and this result should not be ignored. In particular, patients with PPI infusion therapy should be monitored more closely.     

Proton pump inhibitors - differences emerge in hepatic metabolism

Differences are emerging with respect to the mode of metabolism of proton pump inhibitors. All, except rabeprazole, are metabolised primarily by the hepatic cytochrome P450 enzyme system, and common genetic polymorphisms of the CYP 2C19 iso-enzyme affect their clearance and bio-availability. This has been demonstrated to lead to inconsistency in terms of acid suppression across the CYP 2C19 genotypes for all proton pump inhibitors except for rabeprazole. Omeprazole and, more markedly, esomeprazole, differ from the other proton pump inhibitors in that their bio-availability increases over the first week of treatment. This is due to a progressive reduction in their hepatic clearance with repeat dosing. This reduced hepatic clearance appears to be due to the S-enantiomer of omeprazole-esomeprazole impairing the activity of hepatic CYP 2C19. The clinical significance of these differences in metabolism of the various proton pump inhibitors, and the possible benefits of the non-enzymatic metabolism of rabeprazole, require further investigation.