Effect Of Proton Pump Inhibitor Use Research Articles

Alterations in gut microbiota and bile acids by proton-pump inhibitor use and possible mediating effects on elevated glucose levels and insulin resistance.

Several observational studies have suggested that proton-pump inhibitor (PPI) use might increase diabetes risk, but the mechanism remains unclear. This study aimed to investigate the effects of PPI use on gut microbiota and bile acids (BAs) profiles, and to explore whether these changes could mediate the association of PPIs use with fasting blood glucose (FBG) levels and insulin resistance (IR) in Chinese population. A cross-sectional study was conducted in Shenzhen, China, from April to August 2021, enrolled 200 eligible patients from the local hospital. Participants completed a questionnaire and provided blood and stool samples. Gut microbiome was measured by16S rRNA gene sequencing, and bile acidswere quantified by UPLC-MS/MS. Insulin resistance (IR) was assessed using the Homeostasis Model Assessment 2 (HOMA2-IR). PPI use was positively associated with higher levels of FBG and HOMA2-IR after controlling for possible confounders. PPI users exhibited a decreased Firmicutes and an increase in Bacteroidetes phylum, alongside higher levels of glycoursodeoxycholic acid (GUDCA) and taurochenodeoxycholic acid (TCDCA). Higher abundances of Bacteroidetes and Fusobacterium as well as higher levels of TCDCA in PPI users were positively associated with elevated FBG or HOMA2-IR. Mediation analyses indicated that the elevated levels of FBG and HOMA2-IR with PPI use were partially mediated by the alterations in gut microbiota and specific BAs (i.e., Fusobacterium genera and TCDCA). Long-term PPI use may increase FBG and HOMA2-IR levels, and alterations in gut microbiota and BAs profiles may partially explain this association.

Proton pump inhibitors, bone and phosphocalcic metabolism

Proton pump inhibitors (PPIs) are widely used for acid-related gastrointestinal disorders; however, concerns have arisen about their prolonged and inappropriate use. Although generally considered safe, recent evidence has linked PPI use with an increased risk of kidney disease, stomach cancer, pneumonia, dementia, cardiovascular events and potential bone health problems. This systematic review examines the effects of PPIs on bone health, including osteoporosis and changes in phosphocalcic and magnesium metabolism, through a comprehensive analysis of the recent literature. The relationship between PPIs, bone mineral density and fracture risk, especially in populations with comorbidities, is complex and we propose a focus based on recent data. Studies of the effect of PPI use on bone mineral density have shown mixed results and require further investigation. Observational studies have indicated an increased risk of fractures, particularly vertebral fractures, associated with PPI use. Recent meta-analyses have confirmed an association between PPI use and hip fractures with a dose-dependent effect. More recently, PPIs have been associated with serious disturbances in phosphocalcic and magnesium metabolism that require careful management and discontinuation. Proton pump inhibitor-induced hypomagnesemia (PPIH) is a well-established phenomenon. In addition, hypocalcemia secondary to severe hypomagnesemia has been described. Despite growing evidence of PPI-related risks, further research is essential to better understand the complex mechanisms, as most data are from observational studies and do not establish a causal relationship. This review emphasizes the need for judicious prescription practices, particularly in long-term use scenarios and rheumatological contexts.

Digestive Tract Cancer-Related Adverse Events Correlated with Proton Pump Inhibitors Use: A Pharmacovigilance Study of the FDA Adverse Event Reporting System

Background. Proton pump inhibitors (PPIs) are widely used to treat digestive system diseases. Previous studies have suggested conflicting results between PPI treatment and the risk for digestive tract cancers (DTCs). This study aimed to assess the effect of PPI use on DTCs by data mining of the FDA Adverse Event Reporting System (FAERS) database. Method. This study examined the correlations between six PPI agents and DTCs by mining the FAERS database from January 2004 to September 2021 by using OpenVigil 2.1. The reporting odds ratio (ROR) defined as the ratio between the odds of reporting a specific adverse event for one drug divided by the corresponding odds for all other drugs, with 95% confidence intervals (CIs), was used to detect statistically significant correlations between PPIs and DTCs. High-level terms (HLTs) and preferred terms (PTs) were defined by the Medical Dictionary for Regulatory Activities 24.0 (MedDRA24.0). Result. A total of 2553 DTC adverse event reports were screened, with positive signals obtained from gastric neoplasms malignant (GNM) (ROR: 1.09, 95% CI: 1.01–1.18) and bile duct neoplasms malignant (BDNM) (ROR: 1.80, 95% CI: 1.44–2.25). Esomeprazole showed the strongest signal (ROR: 1.85, 95% CI: 1.66–2.06) for GNM, while rabeprazole for BDNM (ROR: 2.94, 95% CI: 1.32–6.56), and female PPI users had a higher risk of BDNM (ROR: 2.44, 95% CI: 1.77–3.35). Among subordinate PTs, adenocarcinoma gastric and the combination of “bile duct cancer” and “cholangiocarcinoma” were highly correlated with PPI use. Conclusion. By mining the FAERS database, we provided important clues for the correlation between PPI use and DTC risk.

Association of proton pump inhibitor use with risk of kidney stones: an analysis of cross-sectional data from the US National Health and Nutrition Examination Survey (2007–2018)

ObjectiveSeveral studies have suggested a potential link between use of proton pump inhibitors (PPIs) and the risk of kidney stones, attributed to alterations in urine mineral levels. Our study aimed...

Proton Pump Inhibitors For HIV+ Patients - A Word Of Caution.

Madam, HIV (human immunodeficiency virus) is on the rise in Pakistan. A Lancet global health modeling study reports that patient registration with the National Aids Control Program (NACP) has risen from 4500 in 2013 to 24331 in 2019 [1]. In HIV+ patients, the gastrointestinal tract is a common site of infection, often leading to anorexia, dysphagia, vomiting, weight loss, and diarrhoea. A study conducted in 2016 showed that 80% of HIV-infected adults had moderate-severe GERD (gastro-oesophageal reflux disorder) symptoms [2]. Physicians often prescribe proton pump inhibitors (PPIs) to treat GERD and stomach or duodenal ulcers. This class of drugs is the most potent inhibitor of gastric acid secretion and is ,unfortunately, prescribed excessively and often inappropriately, regardless of if the patient is HIV+. A recent study shows that 66.2% of patients in a tertiary care hospital in Karachi, Pakistan receive PPIs without proper indication [3]. However, PPIs being prescribed inappropriately pose severe health risks to individuals that are HIV+. A recent study in 2019 raised the valid concern that the use of PPIs in patients already receiving anti-retroviral (ARV) therapy in HIV+ patients could very well be related to an increased risk of acute kidney infection (AKI) [4]. This is not the only research to show the adverse effect of PPI use in HIV patients. A 2017 study shows statistically significant increased innate immune activation due to the translocation of microbial products in HIV+ patients taking PPIs [5]. This can carry serious future implications for these patients post-treatment because higher levels of innate immune activation markers are associated with immunological failure in HIV-treated patients [6]. These statistics raise a very critical question- is it safe for PPIs to be prescribed so freely without any attention to patients being HIV+ or on ARV therapy? It is suggested that existing and future ARV therapies be planned carefully if PPIs are prescribed, and close attention be paid to a patient’s virologic response. In the case of acute hospital admission, where PPIs are prescribed for preventing stress-induced or GI ulcers, medication reconciliation algorithms that acknowledge the interaction between protease inhibitors (PIs) and PPIs should be used [7]. It would be prudent to use PPIs strictly when prescribed and for lesser periods of time.

The Effect of Proton Pump Inhibitor Use on Survival of Patients With Colorectal Cancer: A Study of a Racially Diverse Population.

Introduction Proton pump inhibitor (PPI) use is increasing in the general population. Chronic PPI use can lead to hypergastrinemia, which has been purported to increase the risk of developing colorectal cancer (CRC). Several studies have failed to report any association between PPI use and the risk of CRC. However, little is known about the effect of PPI use on CRC survival. In this retrospective analysis, we studied the effect of PPI use on CRC survival in a racially diverse population. Methods Data were abstracted for 1050 consecutive patients diagnosed with CRC from January 2007 to December 2020. The Kaplan-Meier curve was created to study the effect of PPI exposure compared to no exposure on overall survival (OS). Univariate and multivariate analyses were performed to investigate predictors of survival. Results Complete data were available for 750 patients with CRC, 52.5% were males, 22.7% were Whites, 60.1% were Asians, and 17.2% were Pacific Islanders. A total of 25.6% of patients had a history of PPI use. Moreover, 79.2% had hypertension, 68.8% had hyperlipidemia, 38.0% had diabetes mellitus, and 30.2% had kidney disease. There was no difference in median OS among PPI users compared to non-users, p value=0.4. Age, grade, and stage were predictors of inferior OS. No significant association was noticed with gender, race, comorbidities, or treatment with chemotherapy. Conclusion In this retrospective analysis of a racially diverse population of CRC patients, we found that PPI use was not associated with worse OS. Until high-quality prospective data are available, physicians should not stop PPIs that are clinically indicated.

Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial

Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P=0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. Wellcome Trust and Department of Health and Social Care.

Investigation of Enterogermina's Protective and Restorative Mechanisms on the Gut Microbiota with PPI, Using SHIME Technology.

Proton pump inhibitors (PPIs) are commonly prescribed medications associated with changes in the gut microbiome and dysbiosis when used long-term. Probiotics, such as Enterogermina® (containing four strains of Bacillus clausii) reduce side effects from triple therapy with PPI+antibiotics. We aim to assess the ability of this probiotic in preventing and/or treating the dysbiosis induced by PPI use. Faecal samples from six healthy donors were used to colonise a Triple-Mucosal-Simulator of the Human Intestinal Microbial Ecosystem® model with added ileal compartment. Changes in the microbial community composition and metabolite production were measured for PPI alone (control), PPI+Enterogermina (preventative), and Enterogermina treatment after PPI (curative). Differences were assessed by one-way ANOVA with Tukey's multiple comparisons test. The model was shown to replicate some of the effects of long-term PPI use. There were significant changes in microbial diversity and an increase in butyrate levels in the preventative and curative arms, indicative of a beneficial effect to gut health. Probiotic use countered some of the effects of PPI use: Streptococcus bovis levels increased in the control arm but reduced following probiotic treatment. These results show that probiotic treatment with B. clausii may have beneficial effects on the gut microbiota following PPI treatment.

Effect of proton pump inhibitors on the risk of chronic kidney disease: A propensity score-based overlap weight analysis using the United Kingdom Biobank.

Background: Proton pump inhibitors (PPIs) are widely used and have been linked to kidney diseases. However, the role of PPI use in the development of chronic kidney disease (CKD) remains unclear. We undertook this study to examine the association between PPI use and the subsequent risk of CKD. Methods: This is a prospective analysis of 462,421 participants free of cancer diagnosis or chronic kidney disease from the United Kingdom Biobank. Self-reported PPI use was recorded using an electronic questionnaire and confirmed by a trained staff. Incident CKD was identified based on the medical history. Overlap propensity score weighting with the Cox model was used to calculate the effect of PPI use on CKD risk. The number needed to harm (NNH) was calculated at 5 and 10years of follow-up. Results: We documented 7,031 cases of CKD over a median follow-up of 8.1years. Overlap propensity score weighting analysis showed that regular PPI users had a 37% higher risk of CKD incident than non-users (HR 1.37, 95% CI 1.28-1.47). The association persisted across subgroup analyses, different types of PPIs, and several sensitivity analyses. Quantitative bias analysis indicated that the result was robust to unmeasured confounding (E-value 2.08, lower 95% CI 1.88). The NNH was 147.9 and 78.6 for 5 and 10years of follow-up, respectively. A head-to-head comparison showed that PPI users had a 19% higher risk of CKD than H2RA users (HR 1.19, 95% CI 1.02-1.39). Conclusion: The regular use of PPI is associated with a higher risk of CKD. Healthcare providers should carefully weigh up the potential benefits against the risk in prescribing PPIs, particularly for patients requiring long-term treatment.

Association between proton-pump inhibitors and the risk of gastric cancer: a systematic review and meta-analysis.

Proton pump inhibitors (PPIs) may be associated with gastric cancer, but studies in recent years have proven still inconsistent results. We conducted a systematic review and meta-analysis to investigate the association between PPI use and gastric cancer. Pubmed, EMBASE, and Cochrane library were searched for studies published up to 15th February 2022. Studies on the association between PPI and the risk of gastric cancer, pooled the odds ratios (ORs) using a random-effects model. The subgroup analysis for study design, site of gastric cancer, and the duration of PPI use was performed. Heterogeneity was assessed using the I2 and Cochran's Q statistics. Sixteen cohorts and case-control studies were included. PPI use was significantly associated with gastric cancer (OR: 1.75, 95% CI: 1.28-2.40). The subgroup analysis found a significant risk increase in non-cardia gastric cancer (OR: 2.14, 95%CI: 1.50-3.07). There was no duration-dependent effect of PPI use and gastric cancer risk (< 1year: OR: 2.56, 95% CI: 1.41-4.64, I2 = 98%; 1-3years: OR: 1.47, 95% CI: 1.26-1.71, I2 = 41%; > 3years: OR: 1.58, 95% CI: 1.16-2.14, I2 = 74%). PPIs were significantly associated with an increased risk of gastric cancer. However, this association does not confirm causation. Several well-design studies are needed to confirm the findings in the future.

S2343 Long-Term Omeprazole Use Causing Critical Electrolyte Derangements

Introduction: Proton-pump inhibitors (PPI) are the mainstay therapy for acid-related gastrointestinal entities. Longstanding PPI use is associated with an increased risk of adverse effects; however, clinically significant side effects, such as metabolic derangements, are rare. Here we highlight a case of critical electrolyte derangements secondary to prolonged omeprazole use. Case Description/Methods: A 61-year-old female with a history of hypertension and GERD presented with intermittent numbness for several months involving bilateral upper extremities. Exam showed no focal neurologic deficits with intact sensation and appropriate motor strength. CT head and cervical spine were unremarkable. Initial labs showed significant electrolyte derangements, including hypokalemia 3.3 mmol/L, hypocalcemia 5.7 mg/dL (0.64 mmol/L ionized), and hypomagnesemia 0.5 mg/dL. TSH, PTH, and 25-hydroxyvitamin D levels were intact (Table). EKG showed normal sinus rhythm with QTc prolongation at 542 ms. Despite aggressive intravenous repletion, her electrolytes remained suboptimal. After evaluation by endocrinology, her symptoms were thought to be secondary to PPI-induced hypomagnesemia. The patient had been taking omeprazole for nearly 20 years after evaluation by ENT for vocal cord hoarseness thought to be secondary to GERD. Patient was transitioned from PPI to an H2 blocker. She underwent EGD which showed mild gastritis with biopsies negative for Helicobacter pylori. Fortunately, her symptoms resolved after electrolyte stabilization with potassium 3.9 mmol/L, calcium 8.8 mg/dL, and magnesium 1.8 mg/dL. She was discharged on famotidine with instructions to follow up with gastroenterology. Discussion: Hypomagnesemia has become an increasingly well-recognized, albeit rare side effect of PPI use. The mechanism is thought to involve interference of TRPM6 and TRPM7 located on apical membranes of enterocytes leading to intestinal malabsorption with resulting hypomagnesemia as well as hypocalcemia and hypokalemia. Interestingly, manifestations of hypocalcemia and hypokalemia can be concealed by calcium and potassium-sparing agents, which was likely the case in our patient who was taking candesartan-hydrochlorothiazide combination therapy for hypertension. Our case demonstrates the importance of limiting chronic PPI therapy given the potential for serious consequences. Increased efforts should be aimed at deprescribing PPI therapy. Table 1. - Electrolyte derangements including hypokalemia, hypocalcemia, and hypomagnesemia, which remained suboptimal despite aggressive repletion. Electrolytes finally stabilized after switching from PPI to H2 blocker Day 0 Day 3 Day 5 Day 6 K+ (mmol/L) 3.3 3.2 3.8 3.9 Ca+2 (mg/dL) 5.7 6.6 7.8 9.5 Mg+2 (mg/dL) 0.5 1.6 1.7 1.6

1580P Effect of combined use of proton pump inhibitors with cisplatin on platinum nephrotoxicity

Cisplatin nephrotoxicity results from renal accumulation of cisplatin via organic cation transporter 2 (OCT2). Since proton pump inhibitors (PPI) are known to inhibit OCT2 activity, it was thought that the combined use of PPI and cisplatin could prevent nephrotoxicity. In this study, we aimed to evaluate the effect of PPI use on nephrotoxicity in patients with head and neck cancer who received concurrent cisplatin with radiotherapy.

Proton pump inhibitor use and the risk of peritoneal dialysis associated peritonitis.

The use of proton-pump inhibitors (PPI) has been associated with an increased risk of developing spontaneous bacterial peritonitis in patients with cirrhosis. Whether PPI use confers a similar risk in developing peritonitis in peritoneal dialysis (PD) patients remains unclear. To assess whether PPI use is associated with an increased risk of PD peritonitis. Patients on PD were retrospectively identified. Data such as PPI use during PD, underlying diagnoses, comorbidities, and baseline serum tests were collected. Univariable and multivariable analysis was conducted using logistic regression to assess whether PPI use and other factors were associated with PD peritonitis. Fifty-seven patients were identified with a median (interquartile range (IQR)) age of 65.0 (51.5-74.0) years. The median (IQR) time on PD was 29.0 (17.5-45.0) months. Twenty-eight patients were on a PPI during PD. Fifty-seven percent of the PPI group went on to develop peritonitis, compared with 31% of patients without PPI exposure (odds ratio (OR) = 2.96; 95% confidence interval (CI): 1.00, 8.78; P = 0.050). Months on PD (OR=1.03; 95% CI: 1.00, 1.06; P = 0.026), serum urea (OR=0.88; 95% CI: 0.80, 0.97; P = 0.017), congestive cardiac failure (OR=5.44; 95% CI: 1.29, 23.00; P = 0.021) and renovascular disease (OR=14.59; 95% CI: 1.68, 126.67; P = 0.015) were identified as possible risk factors for peritonitis on univariable analysis. Following adjustment for covariates, serum urea, but not PPI use, was associated with PD peritonitis (OR=0.87; 95% CI: 0.78, 0.98; P = 0.020). PPI use during PD was not associated with peritonitis. Due to the small number of patients and the limited number of studies investigating the effect of PPI use on PD peritonitis, further research is needed.

Associations Between Asthma Diagnosis/Asthma Exacerbation and Previous Proton-Pump Inhibitor use: A Nested Case-Control Study Using a National Health Screening Cohort.

Background: Proton-pump inhibitors (PPIs) block acid secretion from gastric parietal cells; however, recent studies have reported that PPIs have antioxidant and anti-inflammatory properties in various cells. Newer PPIs are stronger inhibitors of acid secretion; however, the anti-inflammatory effects of these drugs have not been assessed. We evaluated anti-inflammatory effect of PPIs on the development of asthma/asthma exacerbation (AE) in a national health screening cohort. Methods: This case-control study comprised 64,809 participants with asthma who were 1:1 matched with controls from the Korean National Health Insurance Service-Health Screening Cohort. Conditional logistic regression analysis was used to evaluate the effect of previous PPI use on an asthma diagnosis in all participants. Unconditional logistic regression was used to assess the effect of PPI use on AE in participants with asthma. These relationships were estimated in a subgroup analysis according to PPI generation. Results: Overall, PPI use increased the risk of asthma diagnosis [adjusted odds ratio (aOR) = 1.29, 95% confidence interval (CI) = 1.23–1.35, p < 0.001]. Use of the first-generation PPIs was associated with asthma (aOR = 1.34, 95% CI = 1.18–1.52, p < 0.001), while use of second-generation PPIs was not (aOR = 0.97, 95% CI = 0.82–1.15, p = 0.748). In contrast, overall PPI use decreased the risk of AE in participants with asthma (aOR = 0.79, 95% CI = 0.75–0.84, p < 0.001), although this effect was observed only for second-generation PPIs (aOR = 0.76, 95% CI = 0.65–0.89, p = 0.001). Conclusion: PPI use increased the risk for subsequent asthma diagnosis. However, this effect was confined to first-generation PPIs. Second-generation PPIs decreased the risk of AE.

Is there an association between proton pump inhibitors and radiomorphometric parameters of the mandible? A preliminary study.

This study aimed to analyze the association between the use of proton pump inhibitors (PPIs) and radiomorphometric parameters of trabecular and cortical bone of the mandible. A total of 64 patients (37 females and 27 males) using PPIs (PPI group) and 64 age- and gender-matched healthy individuals (control group) were included in this study. The analyzed radiomorphometric parameters were fractal dimension (FD), mandibular cortical width (MCW), and mandibular cortical index (MCI). There were no significant differences in the mean FDs of selected regions and MCW between the two groups (p > 0.05). The mean MCW was 1.95mm in the PPI group and 2mm in the control group. The MCI C3 category, which represents the most porous state of the mandibular cortex, was 2.5 times more frequent in the PPI group (p = 0.002). PPI use duration did not correlate with FD or MCW. No significant differences were observed in FD, MCW, and MCI distribution according to PPI type (p > 0.05). Although not all radiomorphometric parameters indicated osteoporotic effects of PPI use, the mandibular cortex of PPI users is prone to erosive defects.

Use of Proton-Pump Inhibitor Is Not Associated with Adverse Clinical Outcomes in COVID-19 Patients: A Territory-Wide Cohort Study

Background. Evidence regarding the use of proton-pump inhibitors (PPIs) in COVID-19 patients remains elusive. Aim. To examine the potential effects of PPI use on the clinical outcomes of COVID-19 patients in a territory-wide cohort. Methods. A retrospective cohort study was performed using data from a territory-wide database in Hong Kong. Patients diagnosed with COVID-19 from 23 January 2020 to 1 January 2021 were identified by virological results. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death. PPI users were identified by PPI use within 12 months prior to their diagnosis of COVID-19. Results. We identified 8,675 COVID-19 patients (mean age 46 years, 49% male, 97.6% of all reported cases in Hong Kong), of which 579 (6.7%) patients had used PPI. PPI users were found to be older, more likely to have comorbidities, concomitant medications and unfavourable laboratory parameters than nonusers. Of the 8,675 COVID-19 patients, 500 (5.8%) developed the primary endpoint. After propensity score (PS) balancing for patients’ demographics, comorbidities, laboratory parameters, and use of medications, PPI use was not found to be associated with the development of primary endpoint in PS weighting (weighted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.82–1.46, P = 0.529 ), and PS matching analysis (weighted HR 0.79, 95% CI 0.56–1.13, P = 0.198 ). Consistent nonassociation was observed after multivariable adjustment (adjusted HR 0.84, 95% CI 0.67–1.06, P = 0.142 ), and in subgroups of current and past PPI users. Conclusion. PPI use is not found to be associated with adverse clinical outcomes in COVID-19 patients. The result remains robust after PS weighting, PS matching, and multivariable adjustment.

Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials

BackgroundAlthough randomized controlled trials (RCTs) have suggested a non-significant increased risk of stroke among proton pump inhibitor (PPI) users, the association has not been confirmed. We evaluated the association between regular use of PPIs and incident stroke and identified population groups at high net risk.MethodsThis is a prospective analysis of 492,479 participants free of stroke from the UK biobank. Incident stroke was identified through linkage to hospital admission and death registries using the International Classification of Diseases (ICD)-10 codes (I60, I61, I63, and I64). We evaluated hazard ratios (HRs) adjusting for demographic factors, lifestyle habits, prevalent comorbidities, concomitant use of medications, and indications of PPIs. We assessed the risk differences (RDs) according to the baseline Framingham Stroke Risk Score. In the meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (from 1988 to 1 June 2020) for randomized trials comparing PPIs with other interventions, placebo, or no treatment on stroke risk. Results were combined using a fix-effect meta-analysis (Mantel-Haenszel method).ResultsWe documented 5182 incident strokes over 3,935,030 person-years of follow-up. Regular PPI users had a 16% higher risk of stroke than non-users (HR 1.16, 95% CI 1.06 to 1.27). The estimated effect was similar to our meta-analysis of nine RCTs (case/participants 371/26,642; RR 1.22, 95% CI 1.00 to 1.50; quality of evidence: moderate). The absolute effect of PPI use on stroke increased with the baseline Framingham Stroke Risk Score, with an RD of 1.34‰, 3.32‰, 4.83‰, and 6.28‰ over 5 years for the lowest, quartile 2, quartile 3, and the highest quartile, respectively.ConclusionsRegular use of PPIs was associated with an increased risk of stroke, with a higher absolute risk observed in individuals with high baseline stroke risk. Physicians should therefore exercise caution when prescribing PPIs. An assessment of the underlying stoke risk is recommended for individualized use of PPIs.

P40.15 Proton Pump Inhibitors, Prior Therapy and Survival in Patients Treated With Immune Checkpoint Inhibitors for Advanced NSCLC

Emerging data suggest that concomitant medications (CM) influence response to immune checkpoint inhibitor (ICI). CM impact the host microbiome which may mitigate tumor-immune responsiveness. Proton pump inhibitor (PPI) use in patients treated with ICI has been associated with worse survival. Few data exist regarding the effect of PPI use in terms of the type of ICI or in the combination of ICI and chemotherapy.

The Clinical Impact of Proton Pump Inhibitors When Co-Administered With Dual Antiplatelet Therapy in Patients Having Acute Myocardial Infarction With Low Risk of Gastrointestinal Bleeding: Insights From the China Acute Myocardial Infarction Registry.

Background: The latest guidelines recommend the use of proton pump inhibitors (PPIs) to minimize gastrointestinal bleeding (GIB) in patients receiving dual antiplatelet therapy (DAPT), even though this co-administration may increase the risk of ischemia due to drug interactions. We have noticed that there are few studies conducted on patients with a lower risk of GIB. Therefore, we investigated the clinical effect of co-administration of PPI on DAPT patients with low GIB risk.Methods and Results: From January 2013 to September 2014, a total of 17,274 consecutive patients on DAPT from 108 hospitals with low risk for GIB in the China Acute Myocardial Infarction (CAMI) registry were analyzed. The primary endpoints were GIB and major adverse cardiovascular and cerebrovascular events (MACCE). Multivariate logistic regression analysis and Cox proportional hazard models were used to assess the effect of PPIs use. Of the analyzed patients, 66.6% (n = 11,487) were treated with PPIs. PPI use did not show an extra gastrointestinal protective effect in patients with low risk for GIB who were hospitalized and on follow-up after 2 years. Moreover, it was associated with an increased risk of stroke during the 2-year follow-up [hazard ratio (HR) 2.072, 95% confidence interval (CI) 1.388–3.091, p = 0.0003] and an increased risk of MI after 6 months (HR 1.580, 95% CI 1.102–2.265, p = 0.0119). We found the same results after propensity score matching.Conclusion: PPI use is prevalent in DAPT patients with low GIB risk. PPIs did not show an extra gastrointestinal protective effect, while an increased risk of stroke was observed during the 2-year follow-up.Clinical Trial Registration:www.clinicaltrials.gov, identifier NCT01874691.

Comprehensive analysis of proton pump inhibitors and risk of digestive tract cancers

BackgroundFor the past two decades, dispute on whether proton pump inhibitor (PPI) leads to digestive tract cancer remains, and emerging studies in recent years still demonstrate inconsistent results, which continues to perpetuate concerns over the safety of PPI use. We performed a systematic review and meta-analysis, with comprehensive evaluation by Bradford Hill criteria of causation, to assess the effect of PPI use on digestive tract cancers. MethodsMedline, Embase and Web of Science databases were searched for observational studies published up to 15th January 2021. Pooled relative risks (RRs) were estimated via random effects models. Cumulative defined daily dose- and duration-risk relationships using restricted cubic spline and fractional polynomial models were investigated. Bradford Hill criteria were applied to evaluate causation. PROSPERO Registration: CRD42020211103. ResultsThirty-two publications containing 4,355,254 participants were included. PPI use is associated with an increased risk of overall digestive tract cancers (RR = 1.63, 95% confidence interval (CI) 1.33 to 2.00). PPI use is correlated with increased risks of gastric cancer (RR = 1.78, 95% CI 1.38 to 2.31), pancreatic cancer (RR = 1.72, 95% CI 1.05 to 2.82) and liver cancer (RR = 1.62, 95% CI 1.04 to 2.52), but not of esophageal cancer (RR = 2.06, 95% CI 0.65 to 6.57) and colorectal cancer (RR = 1.24, 95% CI 0.93 to 1.66). The association between PPI and digestive tract cancers is stronger in people with minimal exposure. When cumulative defined daily dose or duration increases, the risks decline and become non-significant. Evaluation by Bradford Hill criteria indicates weak evidence of causation. ConclusionsA causal relationship between PPI use and digestive tract cancers is not supported by the evidence in the current review. Concerns over carcinogenic side-effects of PPI might be unfounded.