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.     

Influence of individual proton pump inhibitors on clinical outcomes in patients receiving clopidogrel following percutaneous coronary intervention

Background:Data are conflicting on whether proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel. We investigated individual PPIs and adverse cardiovascular events in postpercutaneous coronary intervention (PCI) patients on dual antiplatelet therapy with clopidogrel.Methods:We searched Ovid-MEDLINE, EMBASE, and Cochrane from inception to March 2020 to identify studies that evaluated the efficacy and safety of clopidogrel added PPIs versus clopidogrel only in post-PCI patient. We extracted data from 28 studies for major adverse cardiovascular endpoints (MACE), myocardial infarction (MI), cardiovascular death, and gastrointestinal bleeding. Risk ratios (RR) and hazard ratios (HR) were pooled separately.Results:Data were extracted on 131,412 patients from the 28 studies included. Concomitant use of PPI with clopidogrel was associated with increased risk of MACE (RR 1.30; 95% confidence interval [CI] 1.15–1.48; P < .001) and MI (RR 1.43; 95% CI 1.25–1.64; P < .001). Random-effects meta-analyses with individual PPIs demonstrated an increased risk of MACE in those taking pantoprazole (RR 1.31; 95% CI 1.07–1.61, P = .01) or lansoprazole (RR 1.35; 95% CI 1.19–1.54, P < .0001) compared with patients not on PPIs. Likewise, in adjusted analyses, the pooled HR of adjusted events for MACEs showed that the increased risk of MACEs was similar for 4 classes of PPIs but not for rabeprazole (HR: 1.32; 95% CI 0.69–2.53, P = .40).Conclusion:The post-PCI patients on dual antiplatelet therapy with clopidogrel in the PPI group were associated with higher risk of MACE and MI. Although the results for rabeprazole were not robust, it was the only PPI that did not yield a significantly increased risk of MACE.     

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。     

不同质子泵抑制剂对冠脉支架术后氯吡格雷抗血小板功能的影响

目的:观察埃索美拉唑、雷贝拉唑、雷尼替丁或法莫替丁对急性冠脉综合症（ACS）患者冠脉支架术后应用氯吡格雷抗血小板功能的影响。方法: 150例行经皮冠状动脉介入治疗（PCI）的ACS患者,入院后给予阿司匹林300 mg/d,氯吡格雷300 mg负荷剂量继以75 mg/d维持剂量抗血小板治疗,并随机分为质子泵抑制剂（PPI）A组（A1组:埃索美拉唑40 mg/d,n=30,A2组:雷贝拉唑20 mg/d,n=30）、H2受体拮抗剂(H2RA)B组（B1组:雷尼替丁300 mg/d,n=30,B2组:法莫替丁40 mg/d,n=30）和空白对照C组（C组:n=30）。采用ELISA法检测血浆CD62P、GPⅡb/Ⅲa含量及电阻抗法检测血小板聚集功能。结果: PPI或H2RA治疗前后,A组、B组与C组相比,上述指标的差值组间比较均无明显统计学差异,A1组、A2组、B1组、B2组与C组相比,治疗前后上述指标的差值组间比较均无统计学差异。结论: 埃索美拉唑、雷贝拉唑、雷尼替丁或法莫替丁对氯吡格雷的抗血小板活性无明显的影响。     

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。     

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.     

Impact of concomitant use of proton pump inhibitors and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome

Background There is great debate on the possible adverse interaction between proton pump inhibitors (PPIs) and clopidogrel. In addition, whether the use of PPIs affects the clinical efficacy of ticagrelor remains less known. We aimed to determine the impact of concomitant administration of PPIs and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Methods We retrospectively analyzed data from a “real world”, international, multi-center registry between 2003 and 2014 (n = 15,401) and assessed the impact of concomitant administration of PPIs and clopidogrel or ticagrelor on 1-year composite primary endpoint (all-cause death, re-infarction, or severe bleeding) in patients with ACS after PCI. Results Of 9,429 patients in the final cohort, 54.8% (n = 5165) was prescribed a PPI at discharge. Patients receiving a PPI were older, more often female, and were more likely to have comorbidities. No association was observed between PPI use and the primary endpoint for patients receiving clopidogrel (adjusted HR: 1.036; 95% CI: 0.903–1.189) or ticagrelor (adjusted HR: 2.320; 95% CI: 0.875–6.151) (P_interaction = 0.2004). Similarly, use of a PPI was not associated with increased risk of all-cause death, re-infarction, or a decreased risk of severe bleeding for patients treated with either clopidogrel or ticagrelor. Conclusions In patients with ACS following PCI, concomitant use of PPIs was not associated with increased risk of adverse outcomes in patients receiving either clopidogrel or ticagrelor. Our findings indicate it is reasonable to use a PPI in combination with clopidogrel or ticagrelor, especially in patients with a higher risk of gastrointestinal bleeding.     

Proton pump inhibitors for the treatment of laryngopharyngeal reflux disease: A protocol for systematic review and meta-analysis

Background:Laryngopharyngeal Reflux disease refers to abnormal reflux of gastric contents through the esophagus into the throat, which irritates and damages the pharyngeal mucosa, and causes corresponding symptoms. Proton Pump Inhibitors are an important class of gastric acid secretion inhibitors after H2 receptor blockers, which can be used clinically to treat peptic ulcer, abnormal gastric acid secretion and other related diseases. The common clinical drugs include omeprazole, lansoprazole, rabeprazole and so on. Clinical practice has shown that Proton Pump Inhibitors have a good therapeutic effect on Laryngopharyngeal Reflux disease, but evidence of evidence-based medicine is lacking. The purpose of this protocol is to systematically evaluate the efficacy and safety of Proton Pump Inhibitors in the treatment of Laryngopharyngeal Reflux disease and to improve the evidence-based basis for the clinical application of Proton Pump Inhibitors in the treatment of Laryngopharyngeal Reflux disease.Methods:English computer retrieval database (PubMed, Embase, Web of Science, the Cochrane Library) and Chinese computer retrieval database (Wanfang Database, VIP Information Chinese Journal Service Platform, Chinese Biomedical Database) . In addition, Baidu Scholar and Google Scholar were manually searched for randomized controlled clinical studies on the treatment of laryngeal reflux disease with Proton Pump Inhibitors from the establishment of the database to July 2020. Two researchers independently extracted and evaluated the data of the included studies, and meta-analysis was conducted on the included literatures with RevMan5.3 software without language restrictions.Results:In this study, the efficacy and safety of Proton Pump Inhibitors in the treatment of Laryngopharyngeal Reflux disease are evaluated by the overall response rate, clinical symptom remission rate and other indicators.Conclusions:This study will provide reliable evidence-based evidence for the clinical application of Proton Pump Inhibitors in the treatment of Laryngopharyngeal Reflux disease.OSF Registration number: DOI 10.17605 / OSF.IO / NY6SC     

Cost-effectiveness and clinical outcomes of intermittent/continuous proton pump inhibitors infusion in high bleeding risk of ulcers: A retrospective observational cohort study

The purpose of this study was to evaluate the clinical outcomes, including patient prognosis and medication expense, of proton pump inhibitors administered by high-dose continuous infusion (HDC, 80 mg loading dose, then 8 mg/h for 72 hours) or non-high-dose intermittent infusion (NHDI, 40 mg qd or 40 mg q12 h, for 3 days) regimens in high-risk patients with bleeding peptic ulcers.In this retrospective cohort study, patients with peptic ulcers and endoscopic hemostasis between January, 2013 and December, 2015 were included. The primary endpoints were rebleeding and mortality rates within 7 days. The secondary endpoints were length of stay (LOS), transfusion units of packed red blood cells (PRBCs), and the number needed to treat.A total of 335 patients met the inclusion criteria during the 3-year follow-up period. The cumulative incidence of rebleeding within 7 days was 20.4% and 11.2% in the HDC and NHDI groups, respectively, with a significant difference (P = .021). The mortality rate was 12.1% and 7.3% in the HDC and NHDI groups, respectively, with no significant difference (P = .136). Univariate Cox proportional hazards model analysis showed that the risk of rebleeding within 7 days in the HDC group was higher than that in the NHDI group. The hazard ratio for HDC vs. NHDI was 1.93 (P = .021). There were significant differences in LOS (P = .034) and PRBC units (P = .005) for risk of rebleeding within 7 days, as well as in transfusion units of PRBCs for mortality rate analysis (p < 0.001), between the HDC and NHDI groups. The results showed that the NHDI regimen could reduce the risk of rebleeding within 7 days in 1 of 11 patients (number needed to treat = 11) and could reduce medication cost by US$ 400 to 800.The NHDI regimen showed a lower risk of rebleeding within 7 days, shorter LOS, and fewer PRBC units than that of the HDC regimen. Receiving NHDI has better cost-effective outcomes than that of HDC for patients with high-risk bleeding peptic ulcers.     

Treatment with proton pump inhibitors in acute non-variceal upper gastrointestinal bleeding: a meta-analysis

Medical therapy is an attractive adjuvant to endoscopic treatment in upper gastrointestinal (UGI) bleeding. This review aims to assess the treatment effects of proton pump inhibitor (PPI) therapy in acute non-variceal UGI bleeding. Outcome measures evaluated were further bleeding, surgery, all-cause deaths, ulcer deaths and non-ulcer deaths. We searched MEDLINE (1966-2002) and EMBASE (1974-2002) using the terms 'gastrointestinal hemorrhage', 'peptic ulcer hemorrhage', 'proton pump inhibitor', 'omeprazole', 'pantoprazole', 'lansoprazole', 'rabeprazole' and 'esomeprazole'. The search was extended to the Cochrane controlled trials registry database, published abstracts from five international gastroenterology conferences, manufacturers of PPI, known contacts and bibliographies from each full-length published report. We included trials published in English and non-English languages. Eligible studies were randomized controlled trials that compared the treatment effects of PPI therapy with placebo or H2 receptor antagonists in patients with acute non-variceal UGI bleeding. Of the 175 articles screened, 26 controlled trials including 4670 subjects (2317 in treatment arm and 2353 in control arm) were analyzed. The methodology, population, intervention, and outcomes of each selected trial were evaluated using duplicate independent review. Disagreements were resolved by consensus. PPI therapy significantly reduced rates of further bleeding (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.40-0.57) and surgery (OR, 0.61; 95% CI, 0.48-0.76). All-cause deaths were unaffected (OR, 1.02; 95% CI, 0.76-1.37). Ulcer deaths showed a significant reduction (OR, 0.58; 95% CI, 0.35-0.96), while non-ulcer deaths showed a significant increase (OR, 1.60; 95% CI, 1.06-2.41) in the PPI therapy group. Sensitivity analysis of 22 trials published in peer-reviewed journals, 10 trials with double-blind design and 19 trials with high quality score and 22 trials using omeprazole in the treatment group showed results similar to those seen in the analysis of all 26 trials, confirming the stability of the conclusions. Subgroup analysis revealed that summary outcome measures were not influenced by control group therapy (placebo vs H2 receptor antagonists) or the use of prior endoscopic treatment to achieve hemostasis (given vs not given). However, the summary treatment effects for further bleeding and need for surgery were significant in only those trials enrolling patients with peptic ulcers having high risk for rebleeding and not in those trials enrolling patients with all causes of UGI bleeding. The summary treatment effects for further bleeding and need for surgery were significant in trials using intravenous as well as oral PPI. However, summary OR for all-cause deaths and non-ulcer deaths in trials using intravenous PPI were higher in the treatment group and not in trials using oral PPI. This raised the possibility of intravenous PPI-therapy-associated non-ulcer deaths in high-risk patients. PPI therapy in acute non-variceal UGI bleeding reduced rates of further bleeding, surgery and deaths caused by ulcer complications. However, non-ulcer deaths were increased. The overall mortality was unaffected. PPI therapy is useful only in a selected group of patients with acute non-variceal UGI bleeding, namely those with peptic ulcers having endoscopic high-risk stigmata for rebleeding.     

Effect of proton pump inhibitors on the outcomes of peptic ulcer bleeding: comparison of event rates in routine clinical practice and a clinical trial

Abstract

Objective. To assess clinical outcomes in patients treated with proton pump inhibitors (PPIs) after endoscopic hemostasis in routine clinical care, and to compare these outcomes to those seen in a randomized controlled trial (RCT) of i.v. esomeprazole. Materials and methods. Patients with peptic ulcer bleeding and endoscopic stigmata of recent hemorrhage, who were treated with i.v. esomeprazole or pantoprazole ≥120 mg/day following therapeutic endoscopy, were identified from 12 hospitals in Spain (n = 539). Outcomes assessed included further bleeding, all-cause mortality and surgery. The results were compared to those of the RCT. Results. Overall, 9.1% (95% confidence interval [CI]: 6.7–11.5) of patients experienced further bleeding within 72 h following initial endoscopy, 14.3% (95% CI: 11.3–17.2) of patients had further bleeding within 30 days and 3.3% (95% CI: 1.8–4.9) of patients died within 30 days. In the RCT, the rate of rebleeding within 72 h was significantly lower in the esomeprazole arm (5.9%) than in the placebo arm (10.3%; p = 0.026). The further bleeding rate in patients treated with esomeprazole in routine clinical practice (7.8%; 95% CI: 4.6–11.1) was between these two values. Similar results were seen with the other outcomes studied. Conclusions. The proportion of patients treated with i.v. esomeprazole in routine clinical practice who experienced further bleeding following endoscopic treatment for peptic ulcer bleeding was between the rates observed in the esomeprazole group and the placebo group in the RCT.     

Proton pump inhibitor use increases hepatic encephalopathy risk: A systematic review and meta-analysis

BACKGROUND Several studies have been conducted to explore the association between the use of proton pump inhibitors (PPIs) and hepatic encephalopathy (HE) risk in patients with liver cirrhosis. However, their results are controversial. AIM To perform a systematic review and meta-analysis to evaluate the HE risk among PPI users. METHODS A systematic search on PubMed, Web of Science, EMBase, and ScienceDirect databases was conducted up to December 31, 2018 for eligible studies involving PPI use and HE risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed or random effects model. Publication bias was evaluated using Begg’s test, Egger’s test, and trim-and-fill method. RESULTS Seven studies with 4574 patients were included in the present meta-analysis. The meta-analysis results indicated a significant association between the PPI use and HE risk (OR = 1.50;95%CI: 1.25-1.75) with low heterogeneity (I2 = 14.2%, P = 0.321). Although publication bias existed when Egger’s tests were used (P = 0.005), the trim-and-fill method verified the stability of the pooled result. Sensitivity analyses suggested that the results of this meta-analysis were robust. CONCLUSION The current evidence indicates that PPI use increases HE risk in patients with liver cirrhosis. Further studies with a large data set and well-designed models are needed to validate our findings.     

Use of proton pump inhibitors during pregnancy and rates of major malformations: a meta-analysis

Proton pump inhibitors are used to treat gastroesophageal reflux, a symptom common in pregnancy. The aim of this study was to systematically analyze the available data on the risk for malformations following use of these agents in the first trimester of pregnancy. Medline, EMBASE, published abstracts, and reference lists were searched for articles reporting on proton pump inhibitor use in pregnancy. Summary relative risks and 95% confidence intervals (95% CI) were calculated using the Mantel-Haenszel method. Five cohort studies met the inclusion criteria for this meta-analysis. With almost 600 exposed pregnancies, the overall relative risk was 1.18 with a 95%CI of 0.72–1.94. In conclusion, proton pump inhibitors do not present a major teratogenic risk when used in recommend doses. These data are reassuring for the countless patients who have used these agents in the early part of their pregnancies.