Proton Pump Inhibitors: Review of Emerging Concerns

First introduced in 1989, proton pump inhibitors (PPIs) are among the most widely utilized medications worldwide, both in the ambulatory and inpatient clinical settings. The PPIs are currently approved by the US Food and Drug Administration for the management of a variety of gastrointestinal disorders including symptomatic peptic ulcer disease, gastroesophageal reflux disease, and nonulcer dyspepsia as well as for prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy. PPIs inhibit gastric acid secretion, and the most commonly associated adverse effects include abdominal pain, diarrhea, and headache. Although PPIs have had an encouraging safety profile, recent studies regarding the long-term use of PPI medications have noted potential adverse effects, including risk of fractures, pneumonia, Clostridium difficile diarrhea, hypomagnesemia, vitamin B₁₂ deficiency, chronic kidney disease, and dementia. These emerging data have led to subsequent investigations to assess these potential risks in patients receiving long-term PPI therapy. However, most of the published evidence is inadequate to establish a definite association between PPI use and the risk for development of serious adverse effects. Hence, when clinically indicated, PPIs can be prescribed at the lowest effective dose for symptom control.     

Examination of Potential Mechanisms To Explain the Association between Proton Pump Inhibitors and Clostridium difficile Infection

Proton pump inhibitors (PPIs) have been associated with Clostridium difficile infection (CDI) in several recent studies. However, other studies have not shown this association, and the mechanism by which PPIs might promote CDI has not been elucidated. We hypothesized two possible mechanisms of causation: first, by raising pH, PPIs may prevent gastric contents from killing C. difficile spores; second, gastric contents of PPI-treated patients may promote germination and outgrowth of C. difficile spores. Survival rates of spores from six different strains of C. difficile in acidic gastric contents were assessed using quantitative cultures on selective media. Germination and outgrowth of spores were assessed by heat shock at 80°C, phase-contrast microscopy, and ethanol shock after incubation for 24 h in the gastric contents of patients and in the gastric, small intestinal, and cecal contents of mice. C. difficile spores survived and remained dormant in nonbilious gastric contents with acidic pH. Germination did not occur in unmodified gastric contents of patients but did occur with the addition of taurocholic acid and amino acids. In mice, germination did not occur in gastric contents but did occur in small intestinal and cecal contents. In summary, C. difficile spores survived in acidic gastric contents and did not undergo germination and outgrowth in gastric contents, probably due to lack of essential germinants, such as taurocholic acid. Our results suggest that the effects of PPIs in the stomach do not contribute to the pathogenesis of CDI.Clostridium difficile is a gram-positive, anaerobic spore-forming bacillus that is the most common infectious cause of health care-associated diarrhea in developed countries (19). The recent emergence of an epidemic strain, termed North American pulsed-field gel electrophoresis type 1, or NAP1, has been associated with large outbreaks of C. difficile infection (CDI) in North America and Europe (14, 15). In addition to traditional risk factors, such as exposure to antibiotics and increased underlying disease severity (19), several recent studies have reported an association between proton pump inhibitors (PPIs) and nosocomial (1, 3, 4, 27) or community-associated (5, 6) CDI. Because PPIs are often used in the absence of clear indications (20), it might be feasible to reduce the use of these agents as a control strategy for C. difficile. However, the role of PPIs in the pathogenesis of CDI is controversial because some studies have not associated PPIs with C. difficile (10, 18, 21, 25) and the mechanisms by which acid-suppressive medications might promote CDI are unclear.Gastric acid provides a host defense by killing ingested pathogens (20). PPIs could promote CDI by raising pH, thereby preventing gastric contents from killing ingested C. difficile. However, C. difficile exists primarily in the acid-resistant spore form in the environment (10), and animal models suggest that spores pass through the stomach and germinate in the small intestine, presumably due to stimulation by bile salts (26). Because bile salts can be detected in low concentrations in the stomachs of healthy volunteers and patients with reflux disease (2, 8), it is plausible that C. difficile spores could germinate in the gastric contents of PPI-treated patients. Germination in the stomach could potentially facilitate colonization by increasing the numbers of actively dividing C. difficile spores reaching the intestinal tracts of susceptible individuals (5, 10). We have previously demonstrated that the vegetative form of C. difficile survives in the gastric contents of PPI-treated patients with pHs greater than 5 (10). In addition, we demonstrated that spores from three strains of C. difficile were not killed in acidic gastric contents (20). Here, we examined the survival rates of spores from six different strains of C. difficile in the gastric contents of hospitalized patients not receiving PPIs and tested the hypothesis that germination occurs in the gastric contents of PPI-treated patients.     

Optimizing Prescribing and Deprescribing of Proton Pump Inhibitors

Prescribing of proton pump inhibitors (PPIs) has markedly increased since their inception more than 30 years ago. The increase is related to inappropriate and long-term prescribing of PPIs, associated with a lack of education and unclear prescribing and deprescribing guidelines. The implementation of prescribing stewardship programs influences the reduction and inappropriate use of this medication. The purpose of this review is to address the gaps that exist regarding the use of PPIs along with determining methods for deprescribing. Guidelines and stewardship programs, along with education, are needed to reduce the adverse health effects of long-term PPI therapy.     

In Vitro Study of the Variable Effects of Proton Pump Inhibitors on Voriconazole

Voriconazole is a broad-spectrum antifungal agent used for the treatment of severe fungal infections. Maintaining therapeutic concentrations of 1 to 5.5 μg/ml is currently recommended to maximize the exposure-response relationship of voriconazole. However, this is challenging, given the highly variable pharmacokinetics of the drug, which includes metabolism by cytochrome P450 (CYP450) isotypes CYP2C19, CYP3A4, and CYP2C9, through which common metabolic pathways for many medications take place and which are also expressed in different isoforms with various metabolic efficacies. Proton pump inhibitors (PPIs) are also metabolized through these enzymes, making them competitive inhibitors of voriconazole metabolism, and coadministration with voriconazole has been reported to increase total voriconazole exposure. We examined the effects of five PPIs (rabeprazole, pantoprazole, lansoprazole, omeprazole, and esomeprazole) on voriconazole concentrations using four sets of human liver microsomes (HLMs) of different CYP450 phenotypes. Overall, the use of voriconazole in combination with any PPI led to a significantly higher voriconazole yield compared to that achieved with voriconazole alone in both pooled HLMs (77% versus 59%; P < 0.001) and individual HLMs (86% versus 76%; P < 0.001). The mean percent change in the voriconazole yield from that at the baseline after PPI exposure in pooled microsomes ranged from 22% with pantoprazole to 51% with esomeprazole. Future studies are warranted to confirm whether and how the deliberate coadministration of voriconazole and PPIs can be used to boost voriconazole levels in patients with difficult-to-treat fungal infections.     

The Effects of Concomitant Use of Proton Pump Inhibitors on Iron Supplements

Iron-deficiency anemia is a growing concern and administration of oral iron may be affected by proton pump inhibitors. This drug interaction is common and often overlooked. Iron absorption requires an acidic environment that may be lowered by concomitant use of proton pump inhibitors. Administration of acidic agents, such as vitamin C or orange juice, along with oral iron, may help improve absorption, avoid the use of acid suppression medications, or provide more oral iron availability in those with iron-deficiency anemia. Nurse practitioners are primary health care providers who can help recognize this common drug interaction and help to improve patient care.     

Endoscopic Submucosal Dissection in the Era of Proton Pump Inhibitors

Endoscopic submucosal dissection (ESD) has the advantage over endoscopic mucosa resection, permitting removal of gastrointestinal neoplasms en bloc, but is associated with relatively high risk of complications. Indications for early gastric cancer (EGC) are expanded: mucosal cancer without ulcer findings irrespective of tumor size; mucosal cancer with ulcer findings ≤3 cm in diameter; and minute submucosal invasive cancer ≤3 cm in size. The indications for early esophageal cancer (EEC) are the tumors confined to the two-third layer of the lamina propria. The EEC lesions spreading more than three-quarter of circumference of the esophagus are at frequent risk of stenosis. The procedures include marking, submucosal injection, circumferential mucosal incision and exforiation of the lesion along the submucosal layer. Complete ESD can achieve a large one-piece resection, allowing precise histological assessment to prevent recurrence. Clinical outcomes of gastric and esophageal ESD have been promising, and the prognosis of EGC patients treated by ESD is likely to be excellent, though further longer follow-up studies are warranted. Notification of perforation risk is essential in particular for esophageal ESD. Bleeding during ESD can be managed with coagulation forceps, and postoperative bleeding may be reduced with routine use of the stronger acid suppressant, proton pump inhibitors.     

Proton Pump Inhibitors and the Risk for Hospital-Acquired Clostridium difficile Infection

ObjectiveTo examine the relationship between proton pump inhibitor (PPI) usage and nosocomial Clostridium difficile infection (CDI) and determine the duration of therapy at which CDI risk increases.Patients and MethodsThis retrospective case-control study included consecutive adult patients in whom nosocomial CDI developed after hospitalization for 3 or more days at one of 2 affiliated hospitals between June 1, 2010, and October 31, 2011. These patients were matched to patients hospitalized within 6 months who did not have CDI development in a 1:2 ratio using age, sex, and antibiotic usage. Potential risk factors for CDI, including PPI use and duration, were evaluated. Multivariate analysis was performed to control for confounding variables and identify risk factors.ResultsA total of 201 patients were evaluated, 67 with CDI and 134 matched controls. Patients in whom CDI developed were more likely to have received a PPI (76% vs 39%; P<.001) and had a longer duration of PPI therapy (median [range], 5 [0-20] days vs 0 [0-11] days; P<.001) than those who did not have CDI development. After controlling for prior hospital admission, intensive care unit admission, admission from a skilled nursing facility, immunosuppression, number of antibiotics received, PPI duration, and time to event via multivariate analysis, PPI duration was found to be a risk factor for CDI (odds ratio, 1.14; 95% CI, 1.02-1.27; P=.018). The probability for CDI was higher when PPI use exceeded 2 days in patients without a prior hospital admission and 1 day in patients with a prior admission.ConclusionThe duration of PPI therapy is significantly associated with CDI. Clinicians should strongly consider restricting PPI use given the short exposure time associated with this increased risk.     

质子泵抑制剂和重症患者的医院获得性肺炎之间的关系

目的研究质子泵抑制剂（PPI）是否为危重患者发生医院获得性肺炎的危险因素。方法收集2002年6月-2009年6月收治的198例重症患者资料,分为使用PPI组（96例）和未使用PPI组（102例）。采用logistic回归分析PPI使用情况和医院获得性肺炎的关系。结果使用PPI组肺炎的发生率较高（26.9%）,尤其是PPI使用时间超过7d者（37.5%）。在不同的多变量logistic回归模型中,分别用APACHEⅡ评分和入住重症监护室原因校正后,使用PPI以及使用天数均是医院获得性肺炎发生的危险因素（P=0.031,OR=2.230,95%CI：1.957～2.947;P=0.002,OR=1.824,95%CI：1.457～2.242）。结论长时间应用PPI可能是增加ICU患者发生医院获得性肺炎的一种风险因素。     

胃底腺息肉与质子泵抑制剂及胃癌的相关性

胃底腺息肉是胃底胃体黏膜形成的单发或多发性广基息肉样隆起,是目前国内外常见的息肉类型.其最初在家族性腺瘤性息肉病患者中被发现,越来越多的报道认为胃底腺息肉与质子泵抑制剂的长期使用相关.然而,国内对于长期接受质子泵抑制剂的患者中胃底腺息肉的发生率和发展情况调查研究较少,二者是否存在联系尚存争议,且胃底腺息肉是否与胃癌相关...     

质子泵抑制剂导致的急性泛发性发疹性脓疱病:基于真实世界的药物警戒研究

  目的  探讨不同质子泵抑制剂(proton pump inhibitors, PPIs)与急性泛发性发疹性脓疱病(acute generalized exanthematous pustulosis, AGEP)的关联性及特点。  方法  检索2004年1月至2020年6月美国食品药品监督管理局不良事件报告系统(Food and Drug Administration's adverse events reporting system, FAERS)数据库中PPIs/AGEP相关报告,采用比例失衡测量法及贝叶斯法对不同PPIs导致的AGEP进行关联性分析,并比较其发病时间及预后。  结果  共检索到此期间PPIs导致的AGEP病例报告162例。应用的PPIs药物主要为奥美拉唑(33.95%,55/162),其次为埃索美拉唑(29.63%,48/162)、泮托拉唑(26.54%,43/162)。以泮托拉唑与AGEP的关联性最强,其次为奥美拉唑和兰索拉唑,埃索美拉唑与AGEP的关联性较弱。PPIs导致AGEP发病时间的中位数为6(2,12)d,60.00%~83.33%的患者于用药后10 d内发病(除雷贝拉唑外)。3例(1.86%)AGEP患者死亡,128例(79.50%)需住院治疗。以埃索美拉唑导致的AGEP患者住院比率最高(91.49%,43/47),其次为泮托拉唑(88.37%,38/43)、兰索拉唑(85.71%,12/44),奥美拉唑(61.82%,34/55)最低。  结论  基于对FAERS数据库的药物警戒研究,揭示不同PPIs导致AGEP的风险及特点,可为临床合理用药提供依据。     

Association of Proton Pump Inhibitors With Higher Risk of Cardiovascular Disease and Heart Failure

ObjectiveTo examine associations of cumulative exposure to proton pump inhibitors (PPIs) with total cardiovascular disease (CVD; composed of stroke, coronary heart disease, and heart failure [HF]) and HF alone in a cohort study of White and African American participants of the Atherosclerosis Risk in Communities (ARIC) study.MethodsUse of PPIs was assessed by pill bottle inspection at visit 1 (January 1, 1987 to 1989) and up to 10 additional times before baseline (visit 5; 2011 to 2013). We calculated cumulative exposure to PPIs as days of use from visit 1 to baseline. Participants (n=4346 free of total CVD at visit 5; mean age, 75 years) were observed for incident total CVD and HF events through December 31, 2016. We used Cox regression to measure associations of PPIs with total CVD and HF.ResultsAfter adjustment for potential confounding variables, participants with a cumulative exposure to PPIs of more than 5.1 years had a 2.02-fold higher risk of total CVD (95% CI, 1.50 to 2.72) and a 2.21-fold higher risk of HF (95% CI, 1.51 to 3.23) than nonusers.ConclusionLong-term PPI use was associated with twice the risk of total CVD and HF compared with nonusers. Our findings are in concordance with other research and suggest another reason to be cautious of PPI overuse.     

Frequency and Outcomes of Concomitant Use of Proton Pump Inhibitors and Clopidogrel after Hospital Discharge

ObjectiveTo assess the frequency of concomitant use of proton pump inhibitors (PPI) in patients treated with clopidogrel, and the potential impact of this use on cardiovascular events.MethodThree-month prospective observational study. All patients taking clopidogrel who were admitted to the study hospital were included in the study. They were split into categories based on whether they had taken the drug concomitantly with PPI upon admission, upon discharge or during follow-up, or if they had not taken the two drugs together at all. Any post-discharge readmissions for cardiovascular events in the three months following the original admission were also recorded.ResultsA total of 134 patients were included in the study. Only 26 patients (19,6%) did not take any PPI. Among 14 patients (10.5%) readmitted because of a cardiovascular event, 13 were taking clopidogrel concomitantly with a PPI (not statistically significant). Most of the readmitted patients presented other risk factors potentially related with cardiovascular events.ConclusionThis study underlines a high concomitant use of PPI with clopidogrel, with no evidence of an increasing risk of readmission due to cardiovascular event potentially related to a drug-drug interaction between these drugs. The study did not identify any readmission related to a gastro-intestinal complication.     

氯吡格雷与质子泵抑制剂联用治疗冠心病安全性的系统评价

目的 对冠心病患者单用氯吡格雷和联合使用氯吡格雷质子泵抑制剂(PPI)的安全性(心血管事件、死亡或胃肠道出血等)进行系统评价.方法 计算机检索Cochrane图书馆、PubMed,EMbase,SSCI,VIP,CNKI及CBM数据库,检索时间均从建库至2010年9月,并追踪已获文献的参考文献:,由2名研究者独立进行质...     

Prevalence and Risk Factors for Inappropriate Continuation of Proton Pump Inhibitors After Discharge From the Intensive Care Unit

ObjectiveTo determine the prevalence and risk factors for inappropriate discharge on proton pump inhibitor (PPI) therapy started in the intensive care unit (ICU) for stress ulcer prophylaxis.Patients and MethodsThis was a retrospective cohort study of adults initiated on treatment with a PPI in any of 9 affiliated ICUs from January 1, 2014, to December 31, 2018. Patients were excluded if they had an appropriate long-term PPI indication. Logistic regression modeling was used to identify characteristics associated with discharge on treatment with an inappropriate PPI.ResultsOf 24,751 patients admitted to an ICU, 4127 were initiated on treatment with a new PPI, with 2467 (60%) lacking a long-term PPI indication. Of these 2467, a total of 1122 (45%) were continued on PPI therapy after transfer to the floor and 668 (27%) were discharged on PPI therapy. On multivariable analysis, risk factors for inappropriate discharge on PPI therapy included having an upper endoscopy (adjusted odds ratio [aOR], 1.70; 95% CI, 1.08-2.66), admission to the surgical compared with medical ICU (aOR, 2.03; 95% CI, 1.32-3.10), and discharge to a nursing home or rehabilitation facility (aOR, 1.43; 95% CI, 1.04-1.96; and aOR, 2.29; 95% CI, 1.62-3.24, respectively).ConclusionAmong patients started on treatment with a PPI in the ICU without an indication for outpatient PPI use, 27% (668 of 2467) were nonetheless discharged on PPI therapy. Medically complex and surgical ICU patients are at increased risk for receiving PPIs without appropriate documented indications, and careful review of medication lists at discharge should occur in these high-risk groups.