Complications of Proton Pump Inhibitor Therapy

doi:10.1053/j.gastro.2017.04.047

Gastroenterology

Volume 153, Issue 1, July 2017, Pages 35-48

https://doi.org/10.1053/j.gastro.2017.04.047 Get rights and content

Safety issues associated with proton pump inhibitors (PPIs) have recently attracted widespread media and lay attention. Gastroenterologists are frequently asked about the appropriateness of PPI therapy for specific patients. Furthermore, some patients may have had PPI therapy discontinued abruptly or inappropriately due to safety concerns. Faced with such a wide variety of potentially serious adverse consequences, prescribers need to evaluate the evidence objectively to discern the likelihood that any reported association might actually be causal. Here, we review many of the proposed adverse consequences of PPI therapy and apply established criteria for the determination of causation. We also consider the potential contribution of residual confounding in many of the reported studies. Evidence is inadequate to establish causal relationships between PPI therapy and many of the proposed associations. Residual confounding related to study design and the overextrapolation of quantitatively small estimates of effect size have probably led to much of the current controversy about PPI safety. In turn, this has caused unnecessary concern among patients and prescribers. The benefits of PPI therapy for appropriate indications need to be considered, along with the likelihood of the proposed risks. Patients with a proven indication for a PPI should continue to receive it in the lowest effective dose. PPI dose escalation and continued chronic therapy in those unresponsive to initial empiric therapy is discouraged.

Section snippets

False Alarms and the Hill Criteria

The current evidence regarding associations of PPI use with adverse long-term outcomes is predominantly based on observational studies. Such epidemiologic studies often trigger “false alarms.”⁸ Reported associations may be false due to inappropriate design or confounding due to poorly adjusted study parameters applied to retrospective analyses. Overzealous conclusions based on weak associations may result in “epidemics” of sensationalized news coverage followed by widespread patient alarm.⁸

Residual Confounding

Although not one of the Hill criteria, confounding is arguably the most important extraneous factor that could best explain many of the putative associations between PPI therapy and adverse outcomes. Specifically, the central question is whether the observed positive associations are due to the effects of a PPI or the reasons why it was prescribed (ie, confounding by indication). Here the main concern is not necessarily the conditions for which the PPI was indicated because they are generally

Methodological Guidance for Future Studies

There has clearly been a substantial rise in the number of published studies on PPI-related adverse effects over the past few years. Despite the large volume, there has been little advance in our understanding of the probable biological rationale for these proposed epidemiological associations, and it has been difficult to develop PPI-prescribing practice guidelines based on the existing data. To address these issues, 2 changes are necessary in this line of research.

First, we need to shift our

Conclusions

Despite the recent alarm generated by some high-profile, newsworthy publications, few (if any) of the recent scare stories have attempted to balance the benefits of PPIs with their alleged risks. PPIs have revolutionized the management of GERD and have been of enormous benefit to patients who are at risk of upper gastrointestinal ulceration and bleeding from aspirin or NSAIDs. Many recent publications have, however, pointed out that a great number of patients are receiving PPIs unnecessarily

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Cited by (328)

Pharmacologic Management of Eosinophilic Esophagitis
2024, Immunology and Allergy Clinics of North America
Good clinical practice recommendations for the diagnosis and treatment of gastroesophageal reflux disease. An expert review from the Asociación Mexicana de Gastroenterología
2024, Revista de Gastroenterologia de Mexico
La enfermedad por reflujo gastroesofágico (ERGE) es muy prevalente en la población general, se presenta con un amplio espectro de manifestaciones clínicas que requiere de un diagnóstico y tratamiento de precisión.
Esta es una revisión de expertos que establece recomendaciones de buena práctica clínica para el diagnóstico y tratamiento personalizado de la ERGE.
Las recomendaciones de buena práctica clínica se generaron por un grupo de expertos en ERGE, miembros de la Asociación Mexicana de Gastroenterología (AMG), después de hacer una extensa revisión de la literatura publicada y de discutir cada recomendación en una reunión presencial. Este documento no pretende ser una guía de práctica clínica con la metodología que este formato requiere.
Un total de 15 expertos en ERGE elaboraron 27 recomendaciones de buena práctica clínica para el reconocimiento de síntomas y complicaciones, uso racional de pruebas diagnósticas y tratamiento médico de los diferentes fenotipos, identificación y manejo de la enfermedad refractaria, de la sobreposición con trastornos funcionales, del tratamiento endoscópico y quirúrgico, así como sobre la ERGE en el embarazo, el adulto mayor y el paciente obeso.
Actualmente, es posible un diagnóstico de precisión en la ERGE que permite prescribir una terapia personalizada en los sujetos con esta condición. Las recomendaciones de buena práctica clínica del grupo de expertos de la AMG presentadas en este documento pretenden ayudar al médico general y al especialista en el proceso del diagnóstico y tratamiento de precisión del paciente con ERGE.
Gastroesophageal reflux disease (GERD) is very prevalent in the general population, with a broad spectrum of clinical manifestations, requiring accurate diagnosis and treatment.
The aim of this expert review is to establish good clinical practice recommendations for the diagnosis and personalized treatment of GERD.
The good clinical practice recommendations were produced by a group of experts in GERD, members of the Asociación Mexicana de Gastroenterología (AMG), after carrying out an extensive review of the published literature and discussing each recommendation at a face-to-face meeting. This document does not aim to be a clinical practice guideline with the methodology such a document requires.
Fifteen experts on GERD formulated 27 good clinical practice recommendations for recognizing the symptoms and complications of GERD, the rational use of diagnostic tests and medical treatment, the identification and management of refractory GERD, the overlap with functional disorders, endoscopic and surgical treatment, and GERD in the pregnant woman, older adult, and the obese patient.
An accurate diagnosis of GERD is currently possible, enabling the prescription of a personalized treatment in patients with this condition. The goal of the good clinical practice recommendations by the group of experts from the AMG presented in this document is to aid both the general practitioner and specialist in the process of accurate diagnosis and treatment, in the patient with GERD.
Peptic ulcer
2023, Medicina Clinica
La enfermedad ulcerosa péptica es una patología frecuente; aunque su incidencia ha disminuido en los últimos años, sigue siendo una causa importante de morbimortalidad asociada a un elevado gasto sanitario. Los factores de riesgo más importantes son la infección por Helicobacter pylori (H. pylori) y el uso de antiinflamatorios no esteroideos. La mayoría de los pacientes con enfermedad ulcerosa péptica permanecen asintomáticos, siendo la clínica más frecuente la dispepsia, a menudo característica (dispepsia ulcerosa). También puede comenzar con complicaciones como hemorragia digestiva alta, perforación o estenosis. La técnica diagnóstica de elección es la endoscopia digestiva alta. El tratamiento con inhibidores de la bomba de protones, la erradicación de H. pylori y evitar el consumo de antiinflamatorios no esteroideos son la base del tratamiento. Sin embargo, la prevención es la mejor estrategia, incluye una adecuada indicación de inhibidores de la bomba de protones, la investigación y tratamiento de H. pylori, evitar los antiinflamatorios no esteroideos o utilizar aquellos menos gastrolesivos.
Peptic ulcer disease is a frequent pathology; although the incidence has decreased in recent years, it continues to be an important cause of morbidity and mortality associated with high healthcare costs. The most important risk factors are Helicobacter pylori (H. pylori) infection and the use of non-steroidal anti-inflammatory drugs. Most patients with peptic ulcer disease remain asymptomatic, with dyspepsia being the most frequent and often characteristic symptom. It can also debut with complications such as upper gastrointestinal bleeding, perforation or stenosis. The diagnostic technique of choice is upper gastrointestinal endoscopy. Treatment with proton pump inhibitors, eradication of H. pylori and avoiding the use of non-steroidal anti-inflammatory drugs are the basis of treatment.
However, prevention is the best strategy, it includes an adequate indication of proton pump inhibitors, investigation and treatment of H. pylori, avoiding non-steroidal anti-inflammatory drugs or using those that are less gastrolesive.
Association of Proton Pump Inhibitor Use With Incident Dementia and Cognitive Decline in Older Adults: A Prospective Cohort Study
2023, Gastroenterology
Prior studies have suggested that proton pump inhibitor (PPI) use is associated with increased risk of dementia; however, these have been limited by incomplete assessment of medication use and failure to account for confounders. Furthermore, prior studies have relied on claims-based diagnoses for dementia, which can lead to misclassification. We investigated the associations of PPI and histamine-2 receptor antagonist (H2RA) use with dementia and cognitive decline.
We conducted a post hoc analysis of ASPirin in Reducing Events in the Elderly (ASPREE), a randomized trial of aspirin in the United States and Australia, including 18,934 community-based adults ≥65 years of all races/ethnicities. Baseline and recent PPI and H2RA use were determined according to review of medications during annual in-person study visits. Incident dementia was defined according to Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, criteria. Secondary endpoints include cognitive impairment, no dementia (CIND) and changes in cognition. Associations of medication use with dementia and CIND outcomes were examined using Cox proportional hazards models. Changes in cognitive test scores were examined using linear mixed-effects models.
Baseline PPI use vs nonuse was not associated with incident dementia (multivariable hazard ratio, 0.88; 95% confidence interval, 0.72–1.08), CIND (multivariable hazard ratio, 1.00; 95% confidence interval, 0.92–1.09), or with changes in overall cognitive test scores over time (multivariable B, −0.002; standard error, 0.01; P = .85). Similarly, no associations were observed between H2RA use and all cognitive endpoints.
In adults ≥65 years of age, PPI and H2RA use were not associated with incident dementia, CIND, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults.
Gastroesophageal Reflux Disease
2023, Primary Care - Clinics in Office Practice
The Reply
2023, American Journal of Medicine

View all citing articles on Scopus

: Conflicts of interest The authors disclose the following: Dr Vaezi receives research support from Sandhill Scientific. Dr Howden has consultancies with Takeda, Aralez, and Pfizer Consumer Health. Dr Yang has no conflicts to disclose.

View full text

Reviews and PerspectivesReviews in Basic and Clinical Gastroenterology and HepatologyComplications of Proton Pump Inhibitor Therapy

Section snippets

False Alarms and the Hill Criteria

Residual Confounding

Methodological Guidance for Future Studies

Conclusions

Gastroenterology

J Am Coll Cardiol

J Hepatol

J Hepatol

Gastroenterology

Revista Da Associacao Medica Brasileira

Gastroenterology

Kidney Int

Am J Med

Lancet Neurol

Biochim Biophys Acta

Lancet

J Hepatol

Transplant Proc

Hum Pathol

Gastroenterology

Dig Liver Dis

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Am J Clin Nutr

Trends in prescription drug use among adults in the United States from 1999–2012

JAMA

National trends in prescription drug expenditures and projections for 2016

Am J Health Syst Pharm

Drug class review: proton pump inhibitors: final report update 5

Portland, OR: Oregon Health & Science University

American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease

Gastroenterology

Guidelines for the diagnosis and management of gastroesophageal reflux disease

Am J Gastroenterol

The environment and disease: association or causation?

Proc R Soc Med

PPIs and clopidogrel: the band plays on

Am J Gastroenterol

False alarms and pseudo-epidemics: the limitations of observational epidemiology

Obstet Gynecol

Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial

Lancet

Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation

N Engl J Med

Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial

JAMA

Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies

Am J Gastroenterol

Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs

JAMA

Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis

Gut

Use of proton pump inhibitors and H2 blockers and risk of pneumonia in older adults: a population-based case-control study

Pharmacoepidemiol Drug Saf

Community acquired pneumonia incidence before and after proton pump inhibitor prescription: population based study

BMJ

Proton-pump inhibitor use and the risk for community-acquired pneumonia

Ann Intern Med

Association between proton pump inhibitors and spontaneous bacterial peritonitis in cirrhotic patients—a systematic review and meta-analysis

Int J Clin Pract

Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis

J Gastroenterol Hepatol

Systematic review of the risk of enteric infection in patients taking acid suppression

Am J Gastroenterol

Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection

Aliment Pharmacol Ther

Long-term proton pump inhibitor therapy and risk of hip fracture

JAMA

Pulmonary manifestations of gastroesophageal reflux disease

Ann Thorac Med

Proton pump inhibitors and hospitalization with hypomagnesemia: a population-based case-control study

PLoS Med

The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis

PLoS One

Proton pump inhibitors and risk of rhabdomyloysis

Drug Saf

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
Complications of Proton Pump Inhibitor Therapy