Proton Pump Inhibitors Users Research Articles

Proton Pump Inhibitor Use and the Efficacy of Chemotherapy in Metastatic Colorectal Cancer: A Post Hoc Analysis of a Randomized Phase III Trial (AXEPT)

Concomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analyzed the differential impact of PPI use on capecitabine and fluorouracil using the data set from the AXEPT trial, a phase III randomized trial that demonstrated the noninferiority of mXELIRI (modified XELIRI: capecitabine plus irinotecan) to FOLFIRI (leucovorin, fluorouracil, and irinotecan), either with or without bevacizumab in patients with metastatic colorectal cancer. Out of the per-protocol set (n = 620), patients with information on concomitant medications (n = 482) were included in this post hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment-by-PPI-use interaction was examined after adjusting for stratification factors. Of the 482 patients, 49 (10.1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival compared with the FOLFIRI group. In contrast, among the nonusers, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group. Similarly, a trend of worse progression-free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in nonusers. Treatment-by-PPI-use interaction was significant for overall survival and progression-free survival. The significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression-free survival suggests that fluorouracil could be a more favorable option than capecitabine for patients with metastatic colorectal cancer using PPIs. This study showed a significant interaction between the use of proton pump inhibitors (PPIs) and the type of fluoropyrimidines. This interaction mainly comes from the positive impact of PPIs in the survival outcomes in the fluorouracil arm rather than a negative impact of PPIs in the capecitabine arm. The possible drug-drug interaction shown in this study suggests that fluorouracil, rather than capecitabine, could be a more appropriate choice of fluoropyrimidine for patients who are taking PPIs in the treatment of metastatic colorectal cancer.

The Risk of Epilepsy after Long-term Proton Pump Inhibitor Therapy

BackgroundPrescription-event monitoring studies have reported incident epilepsy or seizures in proton pump inhibitor (PPI) recipients. We examined the risk of epilepsy after prolonged PPI exposure and determine what age group was at higher risk of epilepsy. MethodsWe performed a case-control study nested within a sample of Taiwan National Health Insurance beneficiaries (n = 1,000,000). PPI users with subsequent epilepsy were selected as the case cohort. Controls were PPI users without subsequent epilepsy, matched for age, sex, PPI use indication, enrollment time, end point time, follow-up period, overall systemic health, and comorbidities. The total dose of PPI was defined as the cumulative defined daily dose (cDDD). Prolonged PPI use was defined as a cDDD > 365. A logistic regression analysis was performed. Population attributable risk was calculated. ResultsEpilepsy occurred 4.13 years after the initiation of PPI use. PPI users with the highest risk of incident epilepsy received a cDDD > 365 [odds ratio = 1.63, 95% confidence interval = 1.37–1.95], followed by 121–365 cDDD (1.33, 1.18–1.51) and 31–120 cDDD (1.15, 1.02–1.29), compared to those receiving a cDDD ≤ 30, after adjusting for potential confounders. Prolonged PPI use increased the risk of epilepsy in all age groups, and the risk was highest for those older than 80 years (3.11, 1.67–5.79). The population attributable risk was 12.2% (> 365 cDDD vs ≤ 30 cDDD). DiscussionProlonged PPI therapy was associated with an increased risk of epilepsy, particularly in the elderly population.

Inappropriate Prescribing of Proton Pump Inhibitors in Outpatient Clinics.

Proton pump inhibitors are the commonly prescribed drugs for acid-related disorders. However, many of those prescriptions are inappropriate in inpatient and outpatient settings according to the recommended guidelines. Many studies have been conducted in inpatient clinics, but data about the appropriateness of proton pump inhibitor prescribing in outpatient clinics are scarce. Therefore, the aim of this study was to determine inappropriate proton pump inhibitor prescribing rates among patients admitted to a tertiary hospital family medicine outpatient clinic. A total of 259 patients (median age = 59 years; 72.6% women) were enrolled into the study and 35.9% of them had no proper indications to utilize proton pump inhibitors. Inappropriate proton pump inhibitor usage rate was significantly higher in patients older than 60 years compared with their younger counterparts (62.4% vs. 37.6%; p = .001). The most frequent reason to use a proton pump inhibitor with nonapproved indications was polypharmacy (41.9%). Despite endoscopic evaluation, 41.9% of the patients received a proton pump inhibitor without an approved indication. A significant proportion of nonindicated prescriptions were a consequence of continued prescribing without re-evaluating patients in outpatient clinics. Consideration of proton pump inhibitor indications according to the guidelines in every admission may prevent inappropriate prescriptions.

INAPPROPRIATE USAGE OF INTRAVENOUS PROTON PUMP INHIBITORS AND ASSOCIATED FACTORS IN A HIGH COMPLEXITY HOSPITAL IN BRAZIL.

Intravenous (IV) use of proton pump inhibitors (PPIs) is advised only in cases of suspected upper gastrointestinal bleeding (UGIB) or impossibility of receiving oral medication, although there has been a persistent practice of their inappropriate use in health institutions. The purpose of our study was to measure the inappropriate use of IV PPIs in a high complexity hospital in Brazil and to estimate its costs. Retrospective study of 333 patients who received IV omeprazole between July and December of 2018 in a high complexity hospital in Brazil. IV omeprazole was found to be appropriately prescribed in only 23.4% patient reports. This medication was administered mainly in cases of suspected UGIB (19.1%) and stress ulcer prophylaxis in patients with high risk of UGIB unable to receive medication orally (18.7%). It was observed a statistically significant association between adequate prescription and stress ulcer prophylaxis in patients with high risk of UGIB unable to receive medication orally; patient nil per os with valid indication for PPIs usage; prescription by intensive care unit doctors; prescription by emergency room doctors; intensive care unit admission; evolution to death; sepsis; and traumatic brain injury (P<0.05). On the other hand, inadequate prescription had a statistically significant association with surgical ward prescription and non-evolution to death (P<0.05). The estimated cost of the vials prescribed inadequately was US$1696. There was a high number of inappropriate IV omeprazole prescriptions in the studied hospital, entailing greater costs to the institution and unnecessary risks.

The Effect of Concomitant Proton Pump Inhibitor and Cabozantinib on the Outcomes of Patients with Metastatic Renal Cell Carcinoma.

Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC. This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry-liquid chromatography method. We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups. In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC. Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context.

Do proton pump inhibitors prevent Barrett's esophagus progression to high-grade dysplasia and esophageal adenocarcinoma? An updated meta-analysis.

Previous research on the association between proton pump inhibitor (PPI) use and the risk of progression to high-grade dysplasia (HGD)/esophageal adenocarcinoma (EAC) in Barrett's Esophagus (BE) patients has generated inconsistent findings. This meta-analysis was performed to clarify the association. We performed a comprehensive search strategy to select relevant studies up to September 2020. Heterogeneity was assessed using the I-squared statistic. Odds ratios (OR) and 95% confidence intervals (CI) were calculated through either fixed-effects or random-effects model. Duration-response was also performed to assess the gain effects of different PPI intake duration. Sensitivity analysis, subgroup analyses, and tests for publication bias or other small-study effects were conducted. Twelve studies with 155,769 subjects were included. The PPI use was associated with the reduced risk of BE progression to HGD/EAC (OR = 0.47, 95% CI = 0.32-0.71). In the duration-response analysis, the estimated OR for decreased risk of HGD/EAC with PPI intake duration of 12months was 0.81 (95% CI = 0.71-0.91). Sensitivity analysis suggested the results of this meta-analysis were stable. No publication bias was detected. PPI use is associated with a decreased risk of HGD/EAC in patients with BE. For further investigation, that more well-designed studies are still needed to elucidate the protective effect of PPI usage on BE patients to prevent HGD/EAC.

Proton pump inhibitors and mandibular bone quality: A preliminary study.

Proton pump inhibitors (PPI) provide a long-lasting anti-acidic effect by inhibiting the proton pump, and they are one of the most commonly prescribed drugs worldwide. PPIs adversely affect the bone structure via deficiency of vitamins and minerals. The aim of this study was to investigate the possible PPI-induced bone changes in the mandible on panoramic radiographs with the methods of fractal analysis and panoramic morphometric indices. Panoramic radiographs of 402 patients were used (201 PPI users, 201 control group). Fractal analysis was performed on 4 regions of interests (ROI): 1- upper part of the ramus, 2- angulus, 3- anterior of the mental foramen, 4- distal of the middle ramus. Also, the panoramic mandibular index (PMI), mandibular cortical width (MCW), and Klemetti index (KI) were performed on radiographs. There were significant differences in terms of ROI3, MCW, and KI between the control and study groups (p < 0.05) while there was no significant difference for ROI1, ROI2, ROI4, and PMI (p > 0.05). Males were severely affected than females. Osteoporotic changes were detected in the trabecular and cortical bone in the mental foramen region in PPI users with fractal analysis and morphometric indices, while there were no differences for mandibular ramus and angulus regions according to fractal analysis.

Use of Proton Pump Inhibitors vs Histamine 2 Receptor Antagonists for the Risk of Gastric Cancer: Population-Based Cohort Study.

Proton pump inhibitors (PPIs) are commonly prescribed medications. Long-term use of PPIs has been suspected to have a provocative effect on gastric cancer. This study was to determine the association between PPI vs histamine 2 receptor antagonist (H2RA) use and the risk of gastric cancer in a region where the risk of this malignancy is high. A population-based cohort study using the Korean National Health Insurance Services Database. The participants with first prescription of PPIs and H2RA with normal esophagogastroduodenoscopy finding from 2004 through 2015 were collected. Among them, 50% of participants were systematic stratified randomly sampled. There were 122,118 users of PPIs or H2RAs who use medication more than cumulative defined daily dose of 180 days. The users were followed up from long-term use threshold until gastric cancer, death from non-gastric cancer cause, gastric surgery, or study end (December 2017). After calculating propensity score weights, we included 39,799 PPI and 38,967 H2RA users. Among the new PPI and H2RA users, we identified 411 cases of incident gastric cancer from 182,643 person-years of follow-up observation and 397 cases from 178,846 person-years of follow-up observation, respectively. Compared with H2RA users, PPI users did not experience significantly different gastric cancer incidence (adjusted hazard ratio, 1.01; 95% confidence interval, 0.88-1.16; P = 0.89). Sensitivity analyses confirmed that gastric cancer incidence did not differ between PPI and H2RA users. In this large study, long-term treatment with PPIs vs H2RAs did not show higher risk of gastric cancer even in a high-risk region.

Proton pump inhibitors and risk of all-cause and cause-specific mortality: A cohort study.

To investigate the association between proton pump inhibitors (PPIs) and both all-cause and cause-specific mortality. We conducted a cohort study using the UK Clinical Practice Research Datalink GOLD database. We compared 733 885 new users of PPIs to 124 410 new users of H2 receptor antagonists (H2Ras). In a secondary analysis we compared 689 602 PPI new users to 1 361 245 nonusers of acid suppression therapy matched on age, sex and calendar year. Hazard ratios for all-cause and cause-specific mortality were estimated using propensity score (PS) weighted Cox models. PPI prescription was associated with increased risk of all-cause mortality, with hazard ratios decreasing considerably by increasing adjustment (unadjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.62-1.69; PS-weighted HR 1.38, 95% CI 1.33-1.44; high-dimensional PS-weighted HR 1.31, 95% CI 1.26-1.37). Short-term associations were observed with mortality from causes where a causal short-term association is unexpected (eg, lung cancer mortality: PS-weighted HR at 6 months 1.77, 95% CI 1.39-2.25). Adjusted hazard ratios were substantially higher when compared to nonusers (PS-weighted HR all-cause mortality 1.96, 95% CI 1.94-1.99) rather than H2RA users. PPI prescription was strongly associated with all-cause and cause-specific mortality. However, the change in hazard ratios (a) by increasing adjustment and (b) between comparator groups indicates that residual confounding is likely to explain the association between poor health outcomes and PPI use, and fully accounting for this using observational data may not be possible.

Effects of Proton Pump Inhibitors on the Small Bowel and Stool Microbiomes.

Proton pump inhibitor (PPI) use is extremely common. PPIs have been suggested to affect the gut microbiome, and increase risks of Clostridium difficile infection and small intestinal bacterial overgrowth (SIBO). However, existing data are based on stool analyses and PPIs act on the foregut. To compare the duodenal and stool microbiomes in PPI and non-PPI users. Consecutive subjects presenting for upper endoscopy without colonoscopy were recruited. Current antibiotic users were excluded. Subjects taking PPI were age- and gender-matched 1:2 to non-PPI controls. Subjects completed medical history questionnaires, and duodenal aspirates were collected using a validated protected catheter. A subset also provided stool samples. Duodenal and stool microbiomes were analyzed by 16S rRNA sequencing. The duodenal microbiome exhibited no phylum-level differences between PPI (N = 59) and non-PPI subjects (N = 118), but demonstrated significantly higher relative abundances of families Campylobacteraceae (3.13-fold, FDR P value < 0.01) and Bifidobacteriaceae (2.9-fold, FDR P value < 0.01), and lower relative abundance of Clostridiaceae (88.24-fold, FDR P value < 0.0001), in PPI subjects. SIBO rates were not significantly different between groups, whether defined by culture (> 103CFU/ml) or 16S sequencing, nor between subjects taking different PPIs. The stool microbiome exhibited significantly higher abundance of family Streptococcaceae (2.14-fold, P = 0.003), and lower Clostridiaceae (2.60-fold, FDR P value = 8.61E-13), in PPI (N = 22) versus non-PPI (N = 47) subjects. These findings suggest that PPI use is not associated with higher rates of SIBO. Relative abundance of Clostridiaceae was reduced in both the duodenal and stool microbiomes, and Streptococcaceae was increased in stool. The clinical implications of these findings are unknown.

Association of proton pump inhibitors and concomitant drugs with risk of acute kidney injury: a nested case–control study

ObjectivesThis study aimed to assess whether the combined use of proton pump inhibitors (PPIs) with non-steroidal anti-inflammatory drugs (NSAIDs) or antibiotics (penicillins, macrolides, cephalosporins or fluoroquinolones) was associated with an...

Association of proton pump inhibitor use with endothelial function and metabolites of the nitric oxide pathway: A cross-sectional study.

Long-term intake of proton pump inhibitors (PPIs) might increase the risk of cardiovascular events. One suggested mechanism is that PPIs inhibit the enzyme dimethylarginine dimethylaminohydrolase (DDAH) and thereby block the degradation of endothelial asymmetrical dimethylarginine (ADMA). Excess ADMA in turn leads to impaired endothelial nitric oxide (NO) generation. So far, this mechanism has only been established in human cell cultures. Previous studies that examined this pathway in human populations measured circulating ADMA and found no association with PPI use and excess plasma ADMA. But in a recent study, plasma ADMA was not correlated with intracellular ADMA. We therefore focused on changes in plasma citrulline as an indicator for potential DDAH inhibition. We analyzed the association between regular daily PPI intake and flow-mediated dilation (FMD) of the brachial artery as well as plasma concentrations of citrulline, arginine, ADMA, and symmetric dimethylarginine using inverse probability weighting to adjust for confounding and censoring. Data of 1298 participants from two independent cohorts of the population-based Study of Health in Pomerania were used. Participants of the population-based Study of Health in Pomerania are a stratified random sample of the study region. Regular daily intake of PPIs. FMD of the brachial artery and plasma concentrations of citrulline, arginine, ADMA, and symmetric dimethylarginine. Eighty-seven participants (57.5% female) were regular daily users of PPIs. In the fully adjusted models, associations were identified for FMD and plasma citrulline concentrations. PPI users revealed a 0.99% (95% CI: -1.96 to -0.02) lower FMD and 3.03µmol/L (95% CI: -4.96 to -1.10) lower plasma citrulline levels as compared to non-users. Our data provide evidence that long-term intake of PPIs might inhibit human DDAH activity, resulting in impaired endothelial NO production and reduced vascular function. In the long run, this might explain an increased risk for cardiovascular diseases associated with long-term PPI use.

The clinicopathological characteristics of gastric polyps and the relationship between fundic gland polyps, Helicobacter pylori infection, and proton pump inhibitors

To explore the clinical characteristics of different types of gastric polyps and the relationship between fundic gland polyps, Helicobacter pylori (HP) infection, and proton pump inhibitor (PPI) use. The clinical data of 186 patients diagnosed with gastric polyps under endoscopy were selected for retrospective analysis, and the clinical data, gastroscopy, polyp histopathology, HP infection, and PPI usage of all subjects were analyzed. Among the 186 patients with gastric polyps, there were significantly more women (131 cases) than men (55 cases), with a ratio of 2.38:1. PPIs were used in 78% of cases for more than 5 years. The pathological types of patients with gastric polyps in this study were fundic gland polyps, hyperplastic polyps, inflammatory fibrous polyps, and adenomatous polyps. Fundic gland polyps were mainly located in the fundus and gastric body, while hyperplastic polyps were mostly located in the gastric body (P<0.05). The positive rate of HP infection in patients with fundic gland polyps was significantly lower than that in patients with other types of polyps (P<0.05). In patients with long-term use of PPIs, the incidence of fundic gland polyps increased significantly (P<0.05). There were significant differences among the different types of gastric polyps in terms of polyp position, shape, and size. The positive rate of HP infection in patients with fundic gland polyps was low. Long-term use of PPIs (>5 years) increased the incidence of fundic gland polyps to some extent. The mechanisms underlying the relationship between gastric polyps, HP infection, and the use of PPIs remain to be further studied.

Correlation of Long Term Proton Pump Inhibitors (PPI) Use with Iron and Vitamin B12 Deficiency Anaemia

The Suppression of gastric acid by long term use of PPI may decrease iron and vitamin B12 absorption and might be causing iron and vitamin B12 deficiency anaemia. This comparative cross-sectional study was conducted among patients with peptic ulcer disease from November 2017 to March 2020; attending in the Internal Medicine department of Bangabandhu Sheikh Mujib Medical University (BSMMU). A total of 80 patients were included and divided into group-A (PPIs user) and group-B (non-PPI user), each group containing 40 patients each. The group-A included patients who were taking PPIs for more than one year and aged from 18 to 70 years and group-B the control group who were not taking PPIs for atleast 1(one) year. The data were analysed by Statistical Package for the Social Sciences (SPSS) version 20.0 (SPSS Inc., Chicago, IL, USA).The study shown that male were 18(45%) and 19(47.5%) in group A and B respectively and female were 22(55%) and 21(52.5%) in group A and B respectively. The mean age of male and female was (year) 45.35 ± 12.46, 44.85 ± 15.24, respectively. Most of the patient took omeprazole 62.5% follwed by, esomeprazole 20%, pantoprazole 12.5%, rabeprazole 5%. About 47.5% of the patient took PPI for more than 2 years, and 52.5% took between 1-2 years. The mean (±SD) haemoglobin (Hb) level was 10.93±2.00 g/dl amongst group-A and 13.16±1.68g/dl in group-B, the difference is statistically significant (P&lt;0.001). The mean serum iron of the PPI users (group-A) was 46.43±22.79, and of non-PPI users (group-B) was 84.95±33.18, the difference between iron level between two group was statistically significant (odds ratio -6.38 ; CI-2.28-17.84 and P-value &lt;0.001). The PPI user group, mean vitamin B12 was 449±166.99 and in non-PPI group it was 432.85±175.93, which was statistically nonsignificant (P-value -1.00). Amongst all the participant low serum concentrations of iron, ferritin and transferrin were found 23(57.5%), 18(45%) and 27(67.5%), respectively in Group-A (PPI user group) and 7(17.5%), 7(17.5%) and 8(20%) respectively in Group-B (PPI-non user).The difference was statistically significant (p&lt;0.05) between the two groups. But the value of TIBC was found to be high in 36 (90.0%) participants in both groups, which was statistically non-significant(p=0.33). Hematocrit (HCT) were low in 35 (87.5%) participants in Group-A and 25(62.5%) in Group-B. The difference was statistically significant (p&lt;0.05). Low MCV was found in 10(25%) in the PPI user group and 4(10%) in the non-user group, whish was statistically non-significant. No significant differences in vitamin B12 concentrations (pg/ml) 449±166.99 vs 432.85±175.93 were found between groups A and group B, respectively. There was a weak negative Pearson’s correlation shown in ascatter diagram between duration of PPI use, and the iron level of group A (n=40) (r=-.311, p=.051). A negligible Pearson’s correlation was seen in the scatter diagram between the duration of PPI use, and vitamin B12 level of group A (r=+.05 p=.977). This study showed a significant decrease in haemoglobin, haematocrit, iron, ferritin, transferrin saturation in participants taking PPIs for more than one year, compared with age and gender-matched controls. No significant change of MCV, TIBC (Total Iron Binding Capacity) and vitamin B12 were noticed between groups. In conclusion, the study found a significant decrease in hematologic indices and iron profile among patients receiving PPIs for longer than one year. There was no substantial change of Vitamin B12 levels was detected between long-term PPIs users and non PPIs user groups. So, from the study it is suggested that judicial prescription of long-term PPIs must be practiced. However, the small sample size and short study duration were the limitation of the study.&#x0D; Bangladesh Med J. 2021 January; 50(1) : 27-32

Anti-Acid Drug Treatment Induces Changes in the Gut Microbiome Composition of Hemodialysis Patients.

Anti-acid drugs, proton pump inhibitor (PPI) and histamine-2 blocker (H2-blocker), are commonly prescribed to treat gastrointestinal disorders. These anti-acid drugs alter gut microbiota in the general population, but their effects are not known in hemodialysis patients. Hence, we investigated the microbiota composition in hemodialysis patients treated with PPIs or H2-blocker. Among 193 hemodialysis patients, we identified 32 H2-blocker users, 23 PPI users, and 138 no anti-acid drug subjects. Fecal samples were obtained to analyze the gut microbiome using 16S RNA amplicon sequencing. Differences in the microbial composition of the H2-blocker users, PPI users, and controls were assessed using linear discriminant analysis effect size and the random forest algorithm. The species richness or evenness (α-diversity) was similar among the three groups, whereas the inter-individual diversity (β-diversity) was different between H2-blocker users, PPI users, and controls. Hemodialysis patients treated with H2-blocker and PPIs had a higher microbial dysbiosis index than the controls, with a significant increase in the genera Provetella 2, Phascolarctobacterium, Christensenellaceae R-7 group, and Eubacterium oxidoreducens group in H2-blocker users, and Streptococcus and Veillonella in PPI users. In addition, compared to the H2-blocker users, there was a significant enrichment of the genera Streptococcus in PPI users, as confirmed by the random forest analysis and the confounder-adjusted regression model. In conclusion, PPIs significantly changed the gut microbiota composition in hemodialysis patients compared to H2-blocker users or controls. Importantly, the Streptococcus genus was significantly increased in PPI treatment. These findings caution against the overuse of PPIs.

Proton pump inhibitor usage reduces sustained viral response rates for veterans with HIV/HCV coinfection on ledipasvir/sofosbuvir: a real-world study from a multicentre VA cohort.

Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. This retrospective study evaluates the effects of acid suppression medications (PPI or H2 -receptor antagonist [H2 B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multicentre veteran cohort. Patients in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015 were included. The odds ratios (OR) of PPI or H2 B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non-random treatment selection for acid suppression medication use. There were 9703 veterans included in our final analysis. After adjustment of other clinical factors, PPI use is associated with a lower SVR in the overall cohort (95.0% vs. 96.1%, OR: 0.86, 95% CI: 0.74-0.99, p=.03, number needed to harm 90.9) and HIV/HCV coinfection subgroup (93.4% vs. 96.9%, OR: 0.47, 95% CI: 0.26-0.85, p=.01, number needed to harm 28.6). This present study reveals PPI use is associated with reduced SVR after LDV/SOF treatment, with a more significant impact in the subgroup of patients with HIV/HCV coinfection. Precautions need to be taken when using PPI and LDV/SOF in this group of patients.

Proton Pump Inhibitors Increase the Risk of Early Biliary Infection After Placement of Percutaneous Transhepatic Biliary Stents

PurposeTo investigate the association between the use of proton pump inhibitors (PPIs) and the risk of early biliary infection (EBI) after the placement of percutaneous transhepatic biliary stents (PTBS) in patients with unresectable malignant biliary obstruction (MBO). Materials and MethodsA total of 136 patients with unresectable MBO (82 males and 54 females) treated with PTBS were included in this multicenter retrospective study. PPIs were prescribed to MBO patients with dyspepsia. The risk factors for EBI were identified by univariate and multivariate analyses. The association between the use of PPIs and EBI was assessed by logistic analyses. ResultsA total of 72 (53%) patients were regular users of PPIs, and 33 (24%) patients developed EBI after PTBS. Univariate and multivariate analyses revealed that diabetes (hazard ratio [HR], 20.3; 95% confidence interval [CI], 5.6–72.9; P <.001), biliary stones (HR, 20.3; 95% CI, 5.6–72.9; P <.001) and PPIs (HR, 4.0; 95% CI, 1.2–12.8; P =.020) were risk factors for EBI. Further analyses of the correlation between the duration of PPIs use and EBI demonstrated that a prolonged use of PPIs significantly increased the risk of EBI (PPIs for <15 days vs 15–30 days: HR, 10.2; 95% CI, 3.1–33.3; P <.001; and PPIs <15 days vs ≥30 days; HR, 20.4; 95% CI, 2.2–192.3; P <.001). ConclusionThe use of PPIs increased the risk of EBI after PTBS in patients with unresectable MBO. Furthermore, the risk of EBI increased with a prolonged duration of PPIs use.

Proton Pump Inhibitors and Fractures in Adults: A Critical Appraisal and Review of the Literature.

Despite the large number of patients worldwide being on proton pump inhibitors (PPIs) for acid-related gastrointestinal disorders, uncertainty remains over their long-term safety. Particularly, the potential side effects of these drugs on bone health have been evaluated in the last years. The purpose of our narrative review is to gather and discuss results of clinical studies focusing on the interactions between PPIs and fracture risk. Data generated mainly from nested case-control studies and meta-analysis suggest that long-term/high-dose PPIs users are characterized by an increased risk of fragility fractures, mainly hip fractures. However, in these studies, the PPIs-induced bone impairment is often not adjusted for different confounding variables that could potentially affect bone health, and exposure to PPIs was reported using medical prescriptions without adherence evaluation. The mechanisms of the PPI-related bone damage are still unclear, but impaired micronutrients absorption, hypergastrinemia, and increased secretion of histamine may play a role. Clinicians should pay attention when prescribing PPIs to subjects with a preexistent high risk of fractures and consider antiosteoporotic drugs to manage this additive effect on the bone. However, further studies are needed to clarify PPIs action on the bone.

Lack of association between proton pump inhibitor use and brain aging: a cross-sectional study

PurposeDue to conflicting scientific evidence for an increased risk of dementia by intake of proton pump inhibitors (PPIs), this study investigates associations between PPI use and brain volumes, estimated brain age, and cognitive function in the general population.MethodsTwo surveys of the population-based Study of Health in Pomerania (SHIP) conducted in Northeast Germany were used. In total, 2653 participants underwent brain magnetic resonance imaging (MRI) and were included in the primary analysis. They were divided into two groups according to their PPI intake and compared with regard to their brain volumes (gray matter, white matter, total brain, and hippocampus) and estimated brain age. Multiple regression was used to adjust for confounding factors. Cognitive function was evaluated by the Verbal Learning and Memory Test (VLMT) and the Nuremberg Age Inventory (NAI) and put in relation to PPI use.ResultsNo association was found between PPI use and brain volumes or the estimated brain age. The VLMT score was 1.11 lower (95% confidence interval: − 2.06 to − 0.16) in immediate recall, and 0.72 lower (95% CI: − 1.22 to − 0.22) in delayed recall in PPI users than in non-users. PPI use was unrelated to the NAI score.ConclusionsThe present study does not support a relationship between PPI use and brain aging.

The Mortality Risk of Proton Pump Inhibitors in 1.9 Million US Seniors: An Extended Cox Survival Analysis

Observational studies have linked proton pump inhibitors (PPIs) with increased risk of mortality and other safety outcomes, in contradiction with a recent PPI randomized controlled trial (RCT). Observational studies may be prone to reverse causality, where deaths are attributed to the treatment rather than the conditions that are treated (protopathic bias). We analyzed an incident drug user cohort of 1,930,728 elderly Medicare fee-for-service beneficiaries to evaluate the PPI-associated risk of death with a Cox regression analysis with time-varying covariates and propensity score adjustments. To correct for protopathic bias which occurs when a given drug is associated with prodromal signs of death, we implemented a lag-time approach by which any study drug taken during a 90-day look-back window before each death was disregarded. Among 1,930,728 study individuals, 80,972 (4.2%) died during a median 3.8 years of follow-up, yielding an overall unadjusted death rate/1000 person-years of 9.85; 14.31 for PPI users and 7.93 for non- users. With no lag-time, PPI use (vs no use) was associated with 10% increased mortality risk (adjusted HR=1.10; 95% CI 1.08-1.12). However, with a lag-time of 90 days, mortality risk associated with PPI use was near zero (adjusted HR=1.01; 95% CI 0.99-1.02). Given the usage patterns of PPIs in patients with conditions that may presage death, protopathic bias may explain the association of PPIs with increased risk of death reported in observational studies.