Elsevier

Digestive and Liver Disease

Volume 50, Issue 9, September 2018, Pages 894-902
Digestive and Liver Disease

Position Paper
Appropriateness in prescribing PPIs: A position paper of the Italian Society of Gastroenterology (SIGE) — Study section “Digestive Diseases in Primary Care”

https://doi.org/10.1016/j.dld.2018.07.004Get rights and content

Abstract

The introduction of proton pump inhibitors (PPIs) into clinical practice about thirty years ago has greatly improved our therapeutic approach to acid-related diseases for their well-recognized efficacy and safety.

Despite the well-defined indications, however, the use of PPIs continues to grow every year in both western and eastern countries and this phenomenon poses serious queries that include the onset of potential adverse effects and the increase in health care costs. The major reason explaining this worrying market expansion is the inappropriate use of PPIs. In order to re-establish a correct use of these effective drugs in daily clinical practice, the Italian Society of Gastroenterology (SIGE), nominated a panel of experts who reviewed the available clinical literature and produced a series of updated position statements on the use of PPIs in clinical practice.

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.

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      Citation 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].

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