Background
Methods
Results
PPIs for GERD
Summary of the current evidence
PPIs for eosinophilic esophagitis (EoE)
Summary of the current evidence
PPIs for H. pylori eradication and peptic ulcer (PU) disease
Summary of the current evidence
PPIs for Zollinger–Ellison syndrome (ZES)
Summary of the current evidence
PPIs for stress ulcer prophylaxis (SUP)
Summary of the current evidence
PPIs for dyspepsia
Summary of the current evidence
PPIs for NSAID-associated symptoms and lesions
Summary of the current evidence
PPIs for corticosteroid users
Summary of the current evidence
PPIs in patients taking anti-platelet or anti-coagulant therapy
Summary of the current evidence
PPIs for PU bleeding
Summary of the current evidence
PPIs in patients with cancer
Summary of the current evidence
PPI use in cirrhosis
Summary of the current evidence
PPIs for pancreatic diseases
Summary of the current evidence
Safety concerns with long-term PPI therapy
Summary of the current evidence
Theoretical Concern | Evidence Summary |
---|---|
Consequences of long-term PPI-induced hypergastrinemia | • PPI-induced hypergastrinemia is enhanced in H. pylori-infected patients [448], where the antisecretory effect is increased • More and higher quality studies are needed to confirm or refute any causal link with gastric cancer [450, 451] • No data support the increased risk of colorectal cancer [452] • Rebound acid hypersecretion (and increased frequency of acid-related symptoms) is of uncertain clinical relevance [83] |
Infectious consequences of long-term PPI-induced hypochlorhydria | • Growing evidence suggests that acid suppression increases the risk of enteric infections by C. difficile [456‐458] and other pathogens [456, 459] • Increased Candida infections in the mouth, esophagus, stomach, and upper small intestine of PPI users have been documented [460] |
Non-infectious consequences of long-term PPI-induced hypochlorhydria | • According to a single case-control study [462], exposure to antisecretory drugs, including PPIs, was associated with an increased rate of subsequent diagnosis of celiac disease, but the biological plausibility is unclear |
Dysbiosis | |
Consequences of long-term PPI-induced hypochlorhydria on electrolyte and nutrient absorption | • Severe symptomatic hyponatremia has been reported as a consequence of the syndrome of inappropriate ADH secretion [465] • Data support an increased risk of developing significant B12 deficiency [466], but this is a clinical concern only in elderly or malnourished patients |
Idiosyncratic reactions to PPIs | • Magnesium intestinal transport is inhibited by PPIs and may lead to rare but potentially life-threatening hypo-magnesiemia [467, 468] • Lansoprazole-induced microscopic colitis has been described [469], with complete resolution after drug discontinuation; however, recent data suggest a class effect [470] • Despite some case reports, epidemiological studies showing an association between PPI intake and acute pancreatitis have given conflicting results [44] |
Theoretical Concern | Evidence Summary |
---|---|
Infectious consequences of long-term PPI-induced hypochlorhydria | |
Bone consequences of long-term PPI therapy | |
Dementia and Alzheimer’s disease | • Although, in a mouse model, very high-dose PPI use increased the level of β-amyloid in the brain [477], human data linking these drugs to development of dementia are conflicting [478, 479] • The risk of development of Alzheimer’s disease in PPI users appears comparable to that of any incident dementia [480] |
Delirium | • PPIs were found to be an independent factor associated with development of delirium in geriatric inpatients [481], likely reflecting poly-pharmacy and drug-to-drug interactions (DDIs) |
Acute myocardial infarction (AMI) | |
Idiosyncratic reactions to PPIs | • PPIs appear to be the most common cause of drug-induced acute interstitial nephritis (AIN). After PPI withdrawal and corticosteroid therapy, almost all patients recovered a normal renal function [486, 487] • There is a small but definite increase in risk of chronic kidney disease in long-term PPI users, likely resulting from undiagnosed or residual PPI-induced AIN [487] • Polymyositis and other myopathies, including the life-threatening condition of rhabdomyolysis, have been described with all PPIs [488, 489] • Immediate and delayed hypersensitivity to PPIs, with cross reactivity amongst the members of the class, has been described [490] |
PPI-drug interactions | • Acid suppression reduces absorption of levothyroxine, ketoconazole, itraconazole, atazanavir, cefpodoxime, enoxacin, and dipyridamole while increasing that of nifedipine, digoxin, and alendronate [400] • Concomitant use of some PPIs with clopidogrel attenuates the antiplatelet effect of clopidogrel, but may not be clinically relevant since there are no clinical differences in the risk for major adverse CV events [401‐403] • Only a few drug interactions (e.g., with diazepam, warfarin, phenytoin, and methotrexate) involving PPIs (mainly omeprazole and lansoprazole) are of clinical significance [401, 403] • DDIs may be more frequent in some patient populations (e.g., AIDS or cancer) [403] |
Discussion
Clinical setting | PPI dose and duration |
---|---|
GERD
| |
Erosive Esophagitis (A/B) | Standard dose PPI therapy for 8-12 weeks |
Erosive Esophagitis (C/D) | Double dose PPI therapy for 8-12 weeks |
NERD | Standard dose PPI therapy for 4-8 weeks |
Long-term Management (both GERD and NERD) | Standard (or half) dose PPI maintenance (continuous, intermittent or on-demand, depending on clinical characteristics of the patient) |
Barrett’s Esophagus | Long-term individually-tailored PPI therapy |
Extra-digestive GERD | Standard or double-dose PPI therapy for at least 12 weeks |
Eosinophilic Esophagitis
| Standard or double dose PPI therapy for 8-12 weeks |
H. pylori Eradication | Double dose, twice daily, PPI therapy for 7-14 days (in combination with antimicrobials) |
Non H. pylori-related PU disease | Standard dose PPI therapy for 4-8 weeks |
Zollinger-Ellison Syndrome
| High-dose (eventually twice daily) long-term PPI therapy |
Stress Ulcer Prophylaxis
in patients with risk factors | Standard PPI therapy by intravenous route only during ICU stay |
Dyspepsia
| |
Uninvestigated Dyspepsia in Patients younger than 45 yrs | Standard or half-dose empiric PPI therapy for 4 weeks |
Functional Dyspepsia (EPS phenotype) | Standard or half dose PPI therapy for 4-8 weeks |
NSAID-gastropathy
| |
Prevention of gastro-duodenal lesions and events | Standard or half-dose PPI therapy, starting form the very first dose of NSAID in patients at GI risk |
Treatment of gastro-duodenal lesions | Standard dose PPI therapy for 8 weeks |
Steroid therapy
| No need for gastroprotection unless used in combination with NSAIDs |
Anti-Platelet Therapy
| Standard dose PPI therapy, starting form the very first dose of antiplatelet agent in patients at GI risk |
Anti-Coagulant Therapy
| No need for gastroprotection unless used in combination with antiplatelet therapy |
PU Bleeding
| Intravenous bolus of 80 mg of the available injectable PPIs, followed by 8 mg/h for 72 hours |
Cirrhosis
| |
Hypertensive gastropathy | No need for acid suppression |
Prevention or/and treatment of esophageal ulcers after sclerotherapy or variceal band ligation | Standard dose PPI therapy for 10 days (longer treatment should be avoided taking into account the risk of spontaneous bacterial peritonitis) |
Pancreatic Diseases
| |
Acute pancreatitis | No benefits from acid suppression |
Chronic pancreatitis | Standard PPI therapy only in patients with steatorrhea, refractory to enzyme replacement therapy |
Conclusions
Acknowledgements
Statement on
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External Reviewers
|
GERD | • Dr. Fabio Baldi (GVM Care & Research, Bologna, Italy) • Professor Fabio Pace (Bolognini Teaching Hospital, Seriate, Milan, Italy) • Professor Michael F. Vaezi (Vanderbilt University Medical Center, Nashville, TN, USA) • Professor Marcelo F. Vela (Mayo Clinic, Phoenix, AZ, USA) |
Eosinophilic esophagitis | • Dr. Alfredo J. Lucendo (Hospital General de Tomelloso, Tomelloso, Spain) • Professor Michael F. Vaezi (Vanderbilt University Medical Center, Nashville, TN, USA) |
Helicobacter pylori infection and PU disease | • Professor Thomas Borody (Centre for Digestive Diseases, Australia) • Professor Xavier Calvet (Autonomous University of Barcelona, Spain) • Professor Dino Vaira (University of Bologna, Italy) |
Zollinger–Ellison syndrome | • Professor Joe Pisegna (University of California at Los Angeles, USA) • Professor Pierre Poitras (University of Montreal, QC, Canada) • Professor Jens F. Rehfeld (University of Copenhagen, Denmark) • Professor Philippe Ruszniewski (University of Paris VII, Paris, France) |
Stress ulcer prophylaxis | • Professor Francis KL Chan, Chinese University, Hong Kong, China • Professor Giustino Varrassi (Schol of Medical Sciences, LUdeS University, La Valletta, Malta) |
Dyspepsia | • Professor Jan Tack (University of Leuven, Belgium) • Professor Nick J Talley (University of Newcastle, NSW, Australia) |
NSAID-associated GI symptoms and lesions | • Professor Angel Lanas (University of Zaragoza, Spain) • Dr. Mario Guslandi (San Raffaele University Hospital, Milan, Italy) • Professor James Scheiman (University of Michigan, Ann Arbor, MI, USA) |
Corticosteroid use | • Professor Angel Lanas (University of Zaragoza, Spain) • Dr. Mario Guslandi (San Raffaele University Hospital, Milan, Italy) • Professor James Scheiman (University of Michigan, Ann Arbor, MI, USA) |
Anti-platelet or anticoagulant therapy | • Professor Xavier Calvet (Autonomous University of Barcelona, Spain) • Professor Angel Lanas (University of Zaragoza, Spain) • Professor James Scheiman (University of Michigan, Ann Arbor, MI, USA) |
PU bleeding | • Professor Francis KL Chan (Chinese University, Hong Kong, China) • Professor Xavier Calvet (Autonomous University of Barcelona, Spain) • Professor Guido Costamagna (Catholic University, Rome, Italy) • Professor Colin Howden, (University of Tennessee, Health Science Center, Memphis, TN, USA) |
Cancer | • Dr. Renato Cannizzaro (Oncology Reference Center, Aviano, Italy) • Professor Stefano Cascinu (University of Modena and Reggio Emilia, Italy) • Professor Rajesh V. Lalla (UConn School of Dental Medicine, Farmington, CT, USA) • PD Dr. Maria Vehreschild (First Department of Internal Medicine and Center for Integrated Oncology, University of Cologne, Germany) |
Cirrhosis | • Professor Piero Amodio (University of Padua, Italy) |
Pancreatic disease | • Professor Luca Frulloni (University of Verona, Italy) • Professor Peter Alan Banks (Harvard Medical School, Boston, MA, USA) |
Safety | • Professor Colin Howden, (University of Tennessee, Health Science Center, Memphis, TN, USA) • Professor George Triadafilopoulos (Stanford University School of Medicine, CA, USA) |