Position PaperAppropriateness in prescribing PPIs: A position paper of the Italian Society of Gastroenterology (SIGE) — Study section “Digestive Diseases in Primary Care”
Introduction
The introduction of proton pump inhibitors (PPIs) in the drug market in 1989, has greatly improved our therapeutic approach to acid-related diseases. Since then, several PPIs have been synthetized and, due to their well-proven efficacy and safety in this field, the use of PPIs has massively increased, whereas the role of surgery has been greatly revised.
The main indications for PPI use are generally evidence-based and universally acknowledged by many scientific societies: treatment of the various forms and complications of gastroesophageal reflux disease (GERD), eradication of Helicobacter pylori (H. pylori) infection in combination with two or more antibiotics, short- and long-term therapy of H. pylori-negative peptic ulcers, healing and prevention of gastric ulcers associated with non-steroidal anti-inflammatory drugs (NSAIDs)/COX-2 selective inhibitors (COXIBs), co-therapy with endoscopic procedures to control upper digestive bleeding and medical treatment of Zollinger Ellison syndrome [1]. Depending on the nature of the disease, PPIs are prescribed for short-term (4–8 weeks) or long-term (>8 weeks) periods, with either continuous, intermittent or on‐demand therapeutic schedules.
Despite the above well-defined indications, however, the use of PPIs continues to grow every year in both western and eastern countries. In adult Americans, the use of PPIs doubled from 3.9% in 1999 to 7.8% in 2012 [2]. Data from the Organization for Economic Cooperation and Development reports that the use of PPIs is increasing, especially in some European countries [3]. Currently, PPIs are the most commonly used drugs in the world.
This phenomenon poses serious queries about the appropriate prescription of these drugs worldwide. In fact, the endless expansion of PPI market shaped important problems for many regulatory authorities for two relevant features: the progressive and irreversible increase of the costs and the greater potential harms for the patients.
In 2007–2008 the global economic burden of PPIs was more than US $ 25 billion and in 2015 the market of a single PPI, esomeprazole, was more than 5 billion US $ in sales worldwide [4]. Recent studies highlight a long list of potential harmful effects associated with PPI therapy including gastrointestinal, cardiovascular, respiratory, renal, cognitive, bone and electrolytic alterations [5]. Notably, when PPIs are appropriately prescribed, their benefits are likely to outweigh their risks, while the opposite occurs when PPIs are inappropriately prescribed and even modest risks become important.
The prevention of gastro-duodenal ulcers in patients without risk factors, the prophylaxis of stress ulcer in non-intensive care units, steroid therapy alone, anti-platelet or anti-coagulant treatment in patients without risk of gastric injury, the over-treatment of functional dyspepsia and a wrong diagnosis of acid-related disorders are the major reasons for the inappropriate use of PPIs [6].
Studies in primary care and emergency settings report that in up to 40% of cases, PPIs are used inappropriately, thus offering little benefit [5]. PPIs are often prescribed in patients discharged from hospital and surprisingly, these medications are frequently continued in the long term by primary care physicians [7]. The rate of chronic PPI therapy is high, after both appropriate and inappropriate prescriptions (62% and 71%, respectively) [8]. An Italian survey addressing the gastroprotection with PPIs in primary care, disclosed an underuse rate of 25%–30% and an overuse rate (young patients without any concomitant risk factor) as high as 57.5% [9].
The inappropriate prescribing of PPIs is therefore high and significantly affects public health costs. In a US hospital, the estimated cost of inpatient and outpatient inappropriate use of PPIs was $12,272 and $59,272, respectively [10]. A recent study showed only 39% of inpatients prescriptions compliant to guidelines, with a significant difference between academic and non-academic hospitals (compliance being 50% vs. 29%, respectively) [11].
Thus, there is the need for a reappraisal of PPI correct indications for both general practitioners and gastroenterologists in order to re-establish a correct use of these effective drugs in daily clinical practice, according to the best evidence-based guidelines.
This paper reflects the position of the Italian Society of Gastroenterology (SIGE) and provides recommendations on the appropriate prescription of PPIs in clinical practice.
Section snippets
Material and methods
We performed a comprehensive literature search of the PubMed, MEDLINE, EMBASE, Scopus, Cochrane Library and Google Scholar electronic databases up to March 2018 on the PPIs indications and appropriateness. The search strategy used the mesh terms: “proton pump inhibitors”, “gastroesophageal reflux disease”. “non-erosive gastroesophageal reflux disease”, “extra-esophageal symptoms of GERD”, “Barrett’s esophagus”, “eosinophilic esophagitis”, “Helicobacter pylori”, “peptic ulcer”, “non-steroidal
Statement 1
In patients with typical GERD symptoms PPIs have to be considered the first-choice therapy. They are effective as short-term treatment (4–8 weeks) in both erosive esophagitis (EE) and non-erosive reflux disease (NERD). (Level of evidence: high; grade of recommendation: strong).
Summary of evidences
Gastric acid mantains a central role in the pathogenesis of many disorders of the upper digestive tract, particularly in GERD. In fact, excessive acid exposure of the distal part of the esophagus has
Statement 5
In patients with eosinophilic esophagitis (EoE) a short-term (8–12 weeks) clinical trial with PPIs should be attempted, because 30%–50% of them respond to such therapy. In this group with PPI-responsive esophageal eosinophilia PPI-REE) a long-term PPI treatment must be arranged. (Level of evidence: moderate; grade of recommendation: strong).
Summary of evidences
EoE is a chronic immune-mediated inflammatory disorder, defined symptomatically by esophageal dysfunction and structurally by
Statement 6
In patients with H. pylori infection PPIs are a key component of all currently adopted eradication regimens. Twice daily doses of these drugs must be given for 7–14 days. (Level of evidence: high; grade of recommendation: strong).
Summary of evidences
A huge medical literature has clearly shown that chronic gastritis and most peptic ulcers have to be considered nowadays as infectious diseases, due to H. pylori which is a germ with an elective tropism for gastric mucosa [48]. Indeed, many studies
Statement 8
Patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin (ASA) are at increased risk of developing gastric ulcers, when several predisposing conditions are present. PPIs have been shown to be the primary short-term therapy (4–8 weeks) to heal these lesions. (Level of evidence: high; grade of recommendation: strong).
Summary of evidences
NSAIDs are among the most widely used classes of drugs, very effective in controlling pain deriving by various inflammatory conditions.
Statement 10
In patients with ulcer bleeding endoscopic procedures represent the mainstay of therapy, but co-administration of PPIs has been shown to be of great help in downgrading the stigmata of recent haemorrhage. They can be given intravenously, in bolus or as continuous infusion, particularly before endoscopy. (Level of evidence: moderate; grade of recommendation: strong).
Summary of evidences
Although endoscopy remains the most useful therapeutic intervention to stop bleeding, the concomitant use of
Statement 11
In critically ill patients admitted in intensive care units (ICUs), who are at risk of stress ulcers, the use of PPIs can prevent the formation of these lesions and their complications, especially bleeding. The clinical situations at highest risk are represented by patients who require mechanical ventilation for more than 48 h and those with coagulopathy. (Level of evidence: moderate; grade of recommendation: strong).
Summary of evidences
Stress ulcer is an acute condition occurring in patients
Statement 12
In patients with acid hypersecretory conditions, namely Zollinger–Ellison syndrome (ZES), PPIs represent the best medical therapy to maintain acid secretion within adequate levels. When surgical removal of the gastrinoma is not possible, antisecretory therapy must be continued indefinitely. (Level of evidence: high; grade of recommendation: strong).
Summary of evidences
ZES is the best characterized acid hypersecretory disorder and is caused by the tumor gastrinoma producing a large amount of
Statement 13
In patients with functional dyspepsia a short-term therapeutic attempt with PPIs (4–8 weeks) can be adopted, particularly in those with epigastric pain syndrome (EPS). However, it is mandatory that physicians re-evaluate their patients in order to avoid PPI overprescription. (Level of evidence: low; grade of recommendation: conditional).
Summary of evidences
Dyspepsia is a common condition seen in daily clinical practice of both general practitioners and gastroenterologists. It is characterized
Statement 15
In patients taking steroids alone, anti-coagulant or anti-platelet agents without any risk factor, bisphosphonate, SSRIs, antibiotics or chemotherapic compounds, as well as in patients with chronic liver disease, multifocal atrophic gastritis or partial gastrectomy, PPIs are not indicated, and their use is inappropriate. (Level of evidence: moderate; grade of recommendation: strong).
Summary of evidences
PPI use is often devoted to indications different from those recommended by expert consensus
Conclusion
PPIs are the most used drugs worldwide for treating acid-related diseases. A lot of digestive and extradigestive adverse effects have been recently reported, but the quality of evidence supporting these findings is low or very low. However, it appears clear that the appropriate prescription of PPIs produces more benefits than risks, while their inappropriate use favors the opposite, that is adverse effects without benefits. Thus, the best rational way for their correct use is to prescribe PPIs
Conflict of interest
None declared.
References (106)
- et al.
The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association
Gastroenterology
(2017) - et al.
Are proton pump inhibitors really so dangerous
Dig Liver Dis
(2016) - et al.
Potential costs of inappropriate use of proton pump inhibitors
Am J Med Sci
(2014) - et al.
Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis
Gastroenterology
(1997) - et al.
Proton pump inhibitor in GORD: an overview of their pharmacology, efficacy and safety
Pharmacol Res
(2009) - et al.
Combined multichannel intraluminal impedance and pH-metry: a novel technique to improve detection of gastro-oesophageal reflux literature review
Dig Liver Dis
(2004) - et al.
Approach to the patient with presumed extraoesophageal GERD
Best Pract Res Clin Gastroenterol
(2013) - et al.
Response of chronic cough to acid-suppressive therapy in patients with gastroesophageal reflux disease
Chest
(2013) - et al.
Partial regression of Barrett’s esophagus by long-term therapy ’with high-dose omeprazole
Gastrointest Endosc
(1996) - et al.
Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett’s esophagus
Clin Gastroenterol Hepatol
(2013)
Eosinophilic oesophagitis: from physiopathology to treatment
Dig Liver Dis
Eosinophilic esophagitis: update in diagnosis and management. Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE)
Dig Liver Dis
Guidelines for the management of Helicobacter pylori infection in Italy: the III Working Group Consensus Report 2015
Dig Liver Dis
Helicobacter pylori-negative duodenal ulcers: prevalence, clinical characteristics, and prognosis—results from a randomized trial with 2-year follow-up
Am J Gastroenterol
Current indications for acid suppressants in Helicobacter pylori-negative ulcer disease
Best Pract Res Clin Gastroenterol
Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis
Gastroenterology
Gastroduodenal disorders
Gastroenterology
Effects of proton-pump inhibitors on functional dyspepsia: a meta-analysis of randomized placebo-controlled trials
Clin Gastroenterol Hepatol
The efficacy of proton pump inhibitors in nonulcer dyspepsia: a systematic review and economic analysis
Gastroenterology
Trends in prescription drug use among adults in the United States from 1999–2012
JAMA
Overutilization of proton-pump inhibitors: what the clinician needs to know
Ther Adv Gastroenterol
Proton-pump inhibitors: understanding the complications and risks
Nat Rev Gastroenterol Hepatol
Appropriateness of treatment recommendations for PPI in hospital discharge letters
Eur J Clin Pharmacol
Hospital use of acid-suppressive medications and its fall-out on prescribing in general practice: a 1-month survey
Aliment Pharmacol Ther
A very high rate of inappropriate use of gastroprotection for nonsteroidal anti-inflammatory drug therapy in primary care: a cross-sectional study
J Clin Gastroenterol
Patterns and predictors of proton pump inhibitor overuse among academic and nonacademic hospitalists
Intern Med
GRADE: an emerging consensus on rating quality of evidence and strength of recommendations
BMJ
Oesophageal motility and bolus transit abnormalities increase in parallel with the severity of gastro-oesophageal reflux disease
Aliment Pharmacol Ther
Hiatal hernia is the key factor determining the lansoprazole dosage required for effective intra-oesophageal acid suppression
Aliment Pharmacol Ther
Optimizing symptom relief and preventing complications in adults with gastro-oesophageal reflux disease
Digestion
NERD: an umbrella term including heterogeneous subpopulations
Nat Rev Gastroenterol Hepatol
The role of nonacid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients off therapy
Am J Gastroenterol
Expert consensus document: advances in the physiological assessment and diagnosis of GERD
Nat Rev Gastroenterol Hepatol
Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and non-erosive reflux disease: study using combined impedance-pH off therapy
Am J Gastroenterol
Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-esophageal reflux disease-like symptoms and endoscopy-negative reflux disease
Cochrane Database Syst Rev
Functional esophageal disorders
Gastroenterology
Gastro-oesophageal reflux disease in primary care: an international study of different treatment strategies with omeprazole. International GORD Study Group
Eur J Gastroenterol Hepatol
A comparison of five maintenance therapies for reflux esophagitis
N Engl J Med
Management of reflux esophagitis: does the choice of proton pump inhibitor matter?
Int J Clin Pract
Meta-analysis: the efficacy of proton pump inhibitors for laryngeal symptoms attributed to gastro-oesophageal reflux disease
Aliment Pharmacol Ther
Pharmacological bases of the medical treatment of gastroesophageal reflux disease
Dig Dis
Gastro-oesophageal reflux treatment for asthma in adults and children
Cochrane Database Syst Rev
Extraesophageal manifestations in gastroesophageal reflux disease
Minerva Gastroenterol Dietol
How many cases of laryngopharyngeal reflux suspected by laryngoscopy are gastroesophageal reflux disease-related
World J Gastroenterol
Extra-esophageal presentation of gastroesophageal reflux disease: new understanding in a new era
Minerva Gastroenterol Dietol
Effective and safe proton pump inhibitor therapy in acid-related diseases — a position paper addressing benefits and potential harms of acid suppression
BMC Med
Proton pump inhibitors are associated with reduced incidence of dysplasia in Barrett's esophagus
Am J Gastroenterol
Proton-pump inhibitor therapy and the development of dysplasia in patients with Barrett’s oesophagus
Med J Aust
Classification of esophageal motor findings in gastro-esophageal reflux disease: conclusions from an international consensus group
Neurogastroenterol Motil
Cited by (27)
Proactive Measures Aimed at Improving Appropriateness of Use of Proton Pump Inhibitors in Clinical Practice
2021, Clinical Gastroenterology and HepatologyAddressing long-term PPI safety
2020, Digestive and Liver DiseaseLatest insights into the hot question of proton pump inhibitor safety – a narrative review
2020, Digestive and Liver DiseaseAppropriateness of proton pump inhibitors treatment in clinical practice: Prospective evaluation in outpatients and perspective assessment of drug optimisation
2020, Digestive and Liver DiseaseCitation Excerpt :We also recorded whether patients had previously undergone upper gastrointestinal endoscopy, and patients who were on PPI treatment for GORD symptoms were categorised into those treated for oesophageal symptoms (i.e., heartburn, regurgitation, non-cardiac chest pain) or for extra-oesophageal manifestations of GORD (e.g., chronic cough, asthma, reflux laryngitis); in this latter group of patients we also recorded whether PPI treatment had been prescribed following an adequate gastroenterological work-up (e.g., PPI trial, endoscopy, 24-hour pH-impedance evaluation) [27–30]. Appropriateness of PPI prescription was assessed according to the most recent recommendations set forth in the 2018 Position Paper of the Italian Society of Gastroenterology (SIGE), that graded the level of evidence and strength of recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [21,31]. Briefly, Table 1 reports the clinical conditions and concomitant medications where long-term PPI treatment is deemed inappropriate on the basis of SIGE recommendations [21].
Harmonising proton pump inhibitors treatment in the specialist setting following the SIGE recommendations
2019, Digestive and Liver Disease