Proton Pump Inhibitors, Kidney Damage, and Mortality: An Updated Narrative Review.

Since their approval by the Food and Drug Administration (FDA) in 1989, proton pump inhibitors (PPIs) have become one of the most highly utilized drugs in the United States, assuming a position as one of the top 10 most prescribed medications in the country. The purpose of PPIs is to limit the amount of gastric acid secreted by the parietal cells via irreversible inhibition of the H+/K+-ATPase pump, therefore maintaining an elevated gastric acid pH of greater than 4 for 15-21 h. Even though PPIs have many clinical uses, they are not without their adverse effects, mimicking achlorhydria. Besides electrolyte abnormalities and vitamin deficiencies, long-term use of PPIs has been linked to acute interstitial nephritis, bone fractures, poor COVID-19 infection outcomes, pneumonia, and possibly an increase in all-cause mortality. The causality between PPI use and increased mortality and disease risk can be questioned since most studies are observational. Confounding variables can greatly affect an observational study and explain the wide-ranging associations with the use of PPIs. Patients on PPIs are generally older, obese, sicker with a higher number of baseline morbidities, and on more medications than the compared PPI non-users. These findings suggest that PPI users are at a higher risk of mortality and complications based on pre-existing conditions. This narrative review aims to update readers on the concerning effects that proton pump inhibitor use can have on patients and give providers a resource to create informed decisions on appropriate PPI use.

Proton pump inhibitors: Understanding the associated risks and benefits of long-term use.

PURPOSE: Proton pump inhibitors (PPIs) are widely prescribed medications. Various adverse clinical effects of PPIs have been reported in the literature, particularly over the past decade. The purpose of this article is to review published data primarily describing adverse effects associated with PPI use and to help clinicians determine which patients may still benefit from therapy despite safety concerns. SUMMARY: Associations between PPIs and the following have been described: bone fracture, acute and chronic kidney disease, gastrointestinal infections, deficiencies in vitamin B12 and magnesium, and coronavirus disease 2019 and respiratory infections. For inclusion in this review, studies must have evaluated potential adverse events associated with PPIs as a primary or secondary objective. Increased risks of bone fracture, acute and chronic kidney disease, gastrointestinal infections, and magnesium deficiency were consistently reported, albeit mostly in studies involving low-quality data (case-control and/or observational studies) and subject to bias. In the only pertinent randomized controlled trial to date, chronic pantoprazole use was associated with a greater risk of enteric infections relative to placebo use; there was no significant between-group difference in any other adverse event evaluated. PPIs continue to be recommended by the American College of Gastroenterology as a first-line treatment for management of gastroesophageal reflux disease and in the acute period following upper gastrointestinal and ulcer bleeding. CONCLUSION: Higher-quality data is needed to better understand PPI-associated risks of the adverse effects listed above. Until then, clinicians may consider greater vigilance with PPI use; however, the data does not demonstrate a need for wide adoption of de-escalation strategies solely out of safety concerns.

Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial.

BACKGROUND & AIMS: Novel, effective treatments for Helicobacter pylori infection are needed. This study evaluated the efficacy of vonoprazan, a potassium-competitive acid blocker, vs standard treatment on H pylori eradication in the United States and Europe. METHODS: In a randomized, controlled, phase 3 trial, treatment-naïve adults with H pylori infection were randomized 1:1:1 to open-label vonoprazan dual therapy (20 mg vonoprazan twice daily; 1 g amoxicillin 3 times daily), or double-blind triple therapy twice a day (vonoprazan 20 mg or lansoprazole 30 mg; amoxicillin 1 g; clarithromycin 500 mg) for 14 days. The primary outcome was noninferiority in eradication rates in patients without clarithromycin- and amoxicillin-resistant strains (noninferiority margin = 10%). Secondary outcomes assessed superiority in eradication rates in clarithromycin-resistant infections, and in all patients. RESULTS: A total of 1046 patients were randomized. Primary outcome eradication rates (nonresistant strains): vonoprazan triple therapy 84.7%, dual therapy 78.5%, vs lansoprazole triple therapy 78.8% (both noninferior; difference 5.9%; 95% confidence interval [CI], -0.8 to 12.6; P < .001; difference -0.3%; 95% CI, -7.4 to 6.8; P = .007, respectively). Eradication rates in clarithromycin-resistant infections: vonoprazan triple therapy 65.8%, dual therapy 69.6%, vs lansoprazole triple therapy 31.9% (both superior; difference 33.9%; 95% CI, 17.7-48.1; P < .001; difference 37.7%; 95% CI, 20.5-52.6; P < .001, respectively). In all patients, vonoprazan triple and dual therapy were superior to lansoprazole triple therapy (80.8% and 77.2%, respectively, vs 68.5%, difference 12.3%; 95% CI, 5.7-18.8; P < .001; difference 8.7%; 95% CI, 1.9-15.4; P = .013). Overall frequency of treatment-emergent adverse events was similar between vonoprazan and lansoprazole regimens (P > .05). CONCLUSION: Both vonoprazan-based regimens were superior to proton pump inhibitor-based triple therapy in clarithromycin-resistant strains and in the overall study population. CLINICALTRIALS: gov; NCT04167670.

Proton pump inhibitor therapy usage and associated hospitalization rates and critical care outcomes of COVID-19 patients.

Proton Pump Inhibitors (PPI) are one of the most prescribed medications in the United States. However, PPIs have been shown to increase the risk of enteric infections. Our study aims to evaluate the correlation between PPI and COVID-19 severity. We performed a retrospective cohort study on patients who tested positive for SARS-CoV-2 from March to August 2020. Patients were categorized based on PPI user status. Primary outcomes included need for hospital or ICU admission and 30-day mortality. Secondary outcomes looked to determine the severity of COVID-19 infection and effect of comorbid conditions. 2,594 patients were reviewed. The primary outcomes of our study found that neither active nor past PPI use was associated with increased hospital admission or 30-day mortality following completion of multivariate analysis. Additionally, there was no association between COVID-19 infection and the strength of PPI dosing (low, standard, high). However, the following covariates were independently and significantly associated with increased admission: age, male gender, diabetes, COPD, composite cardiovascular disease, kidney disease, and obesity. The following covariates were associated with increased mortality: age, male gender, COPD, and kidney disease. In conclusion, the high risk features and comorbidities of PPI users were found to have a stronger correlation to severe COVID-19 infection and poor outcomes as opposed to the use of PPI therapy.

Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial.

BACKGROUND: Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. METHODS: The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. DISCUSSION: The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. TRIAL REGISTRATION: EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). CLINICALTRIALS: gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).

Use of proton pump inhibitors are associated with higher mortality in hospitalized patients with COVID-19.

BACKGROUND: The adverse effects of proton pump inhibitors (PPIs) on pneumonia have been well reported. However, the relationship between the use of PPIs and the adverse outcomes of coronavirus disease 2019 (COVID-19) is currently inconclusive. In this study, we aimed to explore the relationship between the use of PPIs and the in-hospital mortality among patients who were laboratory-confirmed SARS-CoV-2. METHODS: Data was derived from 2 hospitals which both were the first batch of SARS-CoV-2 specialist hospitals with four types of sensitivity analyses. This cohort included 4634 patients older than 18 years who were laboratory-confirmed SARS-CoV-2. Endpoints were death in hospital (primary) and the recovery of COVID-19 (secondary: the time of COVID-19 nucleic acid testing turning negative). RESULTS: In the entire cohort, there were 3588 non-users, 399 ≤ 0.5 defined daily dose (DDD) PPIs users, 483 1 DDD users, and 164 ≥ 1.5 DDD users. The multivariate logistic regression analysis (odds ratio (OR) = 3.63, 95% confidence interval (CI) = 1.83-7.23, P = 0.0002) and four types of sensitivity analyses showed higher mortality in patients using PPIs during hospitalization, while the relationship between different PPIs dosages and the hospital mortality remained insignificant. Usage of the PPIs significantly prolongs the time of COVID-19 nucleic acid testing turning negative. CONCLUSIONS: The use of PPIs may increase the risk of in-hospital death of patients who were laboratory-confirmed SARS-CoV-2, which means that physicians may need to re-evaluate the benefit-risk assessment of the use of PPIs during the COVID-19 pandemic.

Pre-hospitalization proton pump inhibitor use and clinical outcomes in COVID-19.

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 may escape the inactivation by gastric acid because of hypochlorhydria caused by proton pump inhibitors (PPIs), which could predispose the patients to severe COVID-19. METHODS: We studied the association between prehospitalization PPI exposure and clinical outcomes among hospitalized COVID-19 patients. RESULTS: A total of 295 hospitalized COVID-19 patients were included in the study. 15.6% of hospitalized COVID-19 patients were on PPIs at home. Mortality among PPI-users was 2.3 times higher than non-users, along with 2.3 times higher risk of acute respiratory distress syndrome after adjusting for confounding variables. CONCLUSION: We found that prehospitalization PPI-exposure is independently associated with worse clinical outcomes, including mortality in COVID-19 patients, regardless of the presence of cardiovascular comorbidities.

Does Proton Pump Inhibitor Use Lead to a Higher Risk of Coronavirus Disease 2019 Infection and Progression to Severe Disease? a Meta-analysis.

The findings of previous research on the association between proton pump inhibitor (PPI) use and the treatment and prevention of coronavirus disease 2019 (COVID-19) are inconsistent. Therefore, this meta-analysis was conducted to clarify the outcomes of patients taking PPIs. This analysis included 14 articles with more than 268,683 subjects. PPI use was not associated with increased or decreased risk of COVID-19 infection (odds ratio [OR] 1.64, 95% confidence interval [CI] = 0.54-5.00, P = 0.39) or mortality (OR = 1.91, 95% CI = 0.86-4.24, P = 0.11). However, PPI use increased the risks of severe disease (OR 1.67, 95% CI = 1.37-2.02, P < 0.00001) and secondary infection (OR 4.62, 95% CI = 2.55-8.39, P < 0.00001). In summary, PPI use was not associated with an increased risk of infection and mortality in COVID-19 but appeared to be associated with an increased risk of progression to severe disease and secondary infection. However, more original studies are urgently needed to further clarify the relationship between PPI use and COVID-19.

Which impact for proton pump inhibitors in SARS-CoV-2 pneumonia.

Identification of risk factors for severe outcome of SARS-CoV-2 infection is an important issue in COVID-19 management. Much attention has been focused on comorbidities as well as drugs taken by patients. Usage of proton pump inhibitors (PPIs) appears to potentially influence disease course. These drugs are known to reduce stomach acid and also modulate the immune system. Their use, prior to and during COVID-19 infection, seems to predispose to the development of more severe pneumonia and therefore to a greater risk of mortality. Instead, the use of histamine receptor 2 antagonists (H2RAs) seems to be associated with a better outcome in patients with COVID-19, in terms of symptoms, risk of intubation and death. As PPIs are essential for treatment of many disorders, usage of these drugs should be balanced considering the benefits and risk ratio, in order to guarantee their correct use for the necessary time. It remains to be clarified whether the detrimental effects, in terms of COVID-19 severe outcome, are due to PPIs or to the underlying disease for which they are administered. New controlled-randomized trials are required to better understand their impact in SARS-CoV-2 infections. *Vanvitelli/Monaldi COVID Group: Adriano Cristinziano, Carolina Delle Donne, Cecilia Calabrese, Fabio Perrotta, Filippo Scialò, Francesco Lassandro, Gennaro Mazzarella, Giorgio Paoli, Leonardo De Luca, Maria Galdo, Miriam Buonincontro, Roberta Cianci, Rosalba Donizzetti, Stefano Sanduzzi Zamparelli, Tullio Valente, Vito D'Agnano, Vittorio Bisogni.

Association of proton-pump inhibitor use with adverse health outcomes: A systematic umbrella review of meta-analyses of cohort studies and randomised controlled trials.

AIMS: The aim was to perform an umbrella review to summarise the existing evidence on proton-pump inhibitor (PPI) use and adverse outcomes and to grade the certainty of evidence. METHODS: Electronic databases were searched up to July 2021 for meta-analyses of cohort studies and/or randomised controlled trials (RCTs). Summary effect sizes from a random-effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance and credibility ceilings were devised to classify the credibility of evidence from meta-analyses of cohort studies, whereas the GRADE approach was used for meta-analyses of RCTs. RESULTS: In meta-analyses of cohort studies, 52 of the 91 examined associations were statistically significant (P ≤ .05). Convincing evidence emerged from main analysis for the association between PPI use and risk of all-site fracture and chronic kidney disease in the elderly population. However, none of these associations remained supported by convincing evidence after sensitivity analyses. The use of PPI is also associated with an increased risk of mortality due to COVID-19 infection and other related adverse outcomes, but the quality of evidence was weak. In meta-analyses of RCTs, 38 of the 63 examined associations were statistically significant. However, no associations were supported by high or moderate-quality evidence. CONCLUSION: This study's findings imply that most putative adverse outcomes associated with PPI use may not be supported by high-quality evidence and are likely to have been affected by underlying confounding factors. Future research is needed to confirm the causal association between PPI use and risk of fracture and chronic kidney disease.

Long-term proton pump inhibitor use is a risk factor for mortality in patients hospitalized for COVID-19

Background and aim: The aim of this study is to evaluate whether the long-term (≥4 weeks) use of proton pump inhibitors (PPIs) is a risk factor for intubation requirement and mortality in patients hospitalized for COVID-19. Materials and methods: In this multicentric retrospective study, a total of 382 adult patients (≥18 years of age) with confirmed COVID-19 who were hospitalized for treatment were enrolled. The patients were divided into two groups according to the periods during which they used PPIs: the first group included patients who were not on PPI treatment, and the second group included those who have used PPIs for more than 4 weeks. Results: The study participants were grouped according to their PPI usage history over the last 6 months. In total, 291 patients did not use any type of PPI over the last 6 months, and 91 patients used PPIs for more than 4 weeks. Older age (HR: 1.047, 95% CI: 1.026­1.068), current smoking (HR: 2.590, 95% CI: 1.334­5.025), and PPI therapy for more than 4 weeks (HR: 1.83, 95% CI: 1.06­2.41) were found to be independent risk factors for mortality. Conclusion: The results obtained in this study show that using PPIs for more than 4 weeks is associated with negative outcomes for patients with COVID-19. Patients receiving PPI therapy should be evaluated more carefully if they are hospitalized for COVID-19 treatment.

Increased ACE2 Levels and Mortality Risk of Patients With COVID-19 on Proton Pump Inhibitor Therapy.

INTRODUCTION: Proton pump inhibitor (PPI) use was recently reported to be associated with increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and worse clinical outcomes. The underlying mechanism(s) for this association are unclear. METHODS: We performed a prospective study of hospitalized coronavirus disease 2019 (COVID-19) patients and COVID-negative controls to understand how PPI use may affect angiotensin-converting enzyme 2 (ACE2) expression and stool SARS-CoV-2 RNA. Analysis of a retrospective cohort of hospitalized patients with COVID-19 from March 15, 2020 to August 15, 2020 in 6 hospitals was performed to evaluate the association of PPI use and mortality. Covariates with clinical relevance to COVID-19 outcomes were included to determine predictors of in-hospital mortality. RESULTS: Control PPI users had higher salivary ACE2 mRNA levels than nonusers, 2.39 ± 1.15 vs 1.22 ± 0.92 (P = 0.02), respectively. Salivary ACE2 levels and stool SARS-CoV-2 RNA detection rates were comparable between users and nonusers of PPI. In 694 hospitalized patients with COVID-19 (age = 58 years, 46% men, and 65% black), mortality rate in PPI users and nonusers was 30% (68/227) vs 12.1% (53/439), respectively. Predictors of mortality by logistic regression were PPI use (adjusted odds ratio [aOR] = 2.72, P < 0.001), age (aOR = 1.66 per decade, P < 0.001), race (aOR = 3.03, P = 0.002), cancer (aOR = 2.22, P = 0.008), and diabetes (aOR = 1.95, P = 0.003). The PPI-associated mortality risk was higher in black patients (aOR = 4.16, 95% confidence interval: 2.28-7.59) than others (aOR = 1.62, 95% confidence interval: 0.82-3.19, P = 0.04 for interaction). DISCUSSION: COVID-negative PPI users had higher salivary ACE2 expression. PPI use was associated with increased mortality risk in patients with COVID-19, particularly African Americans.

Proton Pump Inhibitor Use Is Not Strongly Associated With SARS-CoV-2 Related Outcomes: A Nationwide Study and Meta-analysis.

BACKGROUND & AIMS: Proton pump inhibitor (PPI) use has been associated with increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe outcomes. However, meta-analyses show unclear results, leading to uncertainty regarding the safety of PPI use during the ongoing coronavirus disease 2019 (COVID-19) pandemic. METHODS: We conducted a nationwide observational study including all SARS-CoV-2 cases (n = 83,224) in Denmark as of December 1, 2020. The association of current PPI use with risk of infection was examined in a case-control design. We investigated the risk of severe outcomes, including mechanical ventilation, intensive care unit admission, or death, in current PPI users (n = 4473) compared with never users. Propensity score matching was applied to control for confounding. Finally, we performed an updated meta-analysis on risk of SARS-CoV-2 infection and COVID-19 mortality attributable to PPI use. RESULTS: Current PPI use was associated with increased risk of infection; adjusted odds ratio, 1.08 (95% confidence interval [CI], 1.03-1.13). Among SARS-CoV-2 cases, PPI use was associated with increased risk of hospital admission; adjusted relative risk, 1.13 (1.03-1.24), but not with other severe outcomes. The updated meta-analysis showed no association between PPI use and risk of infection or mortality; pooled odds ratio, 1.00 (95% CI, 0.75-1.32) and relative risk, 1.33 (95% CI, 0.71-2.48). CONCLUSIONS: Current PPI use may be associated with an increased risk of SARS-CoV-2 infection and hospital admission, but these results with minimally elevated estimates are most likely subject to residual confounding. No association was found for severe outcomes. The results from the meta-analysis indicated no impact of current PPI use on COVID-19 outcomes.