Proton pump inhibitors: too much of a good thing?

• Review patients taking a PPI long term to evaluate if indication persists – daily, long-term use is only recommended in selected groups.
  
• Consider risks of PPI use particularly in higher-risk groups such as older people.
  
• Discuss with patients the expected initial duration of PPI therapy and plans for stepping down.
  
• Consider stepping down PPI therapy in GORD patients once symptoms are well controlled.
  
• Review use of concomitant medicines and advise patients about those that may exacerbate heartburn or reflux symptoms.
  
• Encourage lifestyle modifications appropriate to the patient.
  

In 2013–14, there were over 19 million prescriptions for PPIs in Australia.¹ Most prescriptions for PPIs are for managing GORD.²

Until the late 20th century, acid–peptic disorders such as gastro-oesophageal reflux disease (GORD) condemned those affected to a lifetime of ineffective dietary restrictions and antacids.⁴ Complications from these disorders were a persistent problem in gastroenterology,⁵ the only effective long-term treatment being surgery.⁶ The discovery of gastric-acid suppressing medicines – H₂-receptor antagonists and proton pump inhibitors (PPIs) – marked a change. Although both classes of medicines provide symptom relief in GORD, PPIs are significantly more effective than H₂ antagonists at relieving symptoms and healing oesophagitis.^7,8

While highly effective with a favourable safety profile, use of PPIs is not without concern. Since their introduction in the early 90s, PPI use has increased by more than 1000% in Australia,² with over 19 million prescriptions in the 2013–14 financial year.¹ Over the last decade, at least two PPIs have featured in the top 10 most prescribed PBS-subsidised medicines every year.^1,9 Not surprisingly, there is growing international concern over their increasing use.^2,10 Long-term use is only recommended in selected populations^11,12 but data indicate that this accounts for most of the total use.¹⁰ Several studies suggest that a substantial proportion of PPI users do not have a clear indication for therapy (Table 1).^13-18

Some reports have linked PPI use to increased risk of fractures, pneumonia, enteric infections, vitamin and mineral deficiencies, and acute interstitial nephritis.^5,19 Although the absolute risk is very low, many of the patients in these reports were older people – a group that makes up the largest proportion of PPI users ² and who are at increased risk of medicine-related problems.²⁰ While there is insufficient evidence to establish causation, these reports deserve consideration.

There are also financial implications of overuse, with extensive costs to both individuals and government. In the 2013–14 financial year, there were close to 7 million PBS-subsidised prescriptions for esomeprazole in Australia, at a cost of over $200 million to the PBS.¹

While PPIs remain a mainstay of management of acid–peptic disorders, the concerns about adverse effects and cost associated with over-prescribing highlight the need for increased attention to their judicious use.

In uncomplicated acid–peptic disorders for which PPI therapy is approved, daily standard-dose therapy (Table 2) is only recommended for initial, short-term treatment.^11,21 Review patients who have been taking a PPI long term to evaluate if ongoing treatment is still indicated.

Table 1: Indications for PPIs and recommended duration of therapy

Continuous, long-term PPI therapy has selective uses

Continuous, long-term PPIs have an important place in the management of some acid-related disorders.

• Symptom management and prevention of complications in patients with GORD who have frequent, significantly troublesome symptoms that are not adequately controlled with step-down therapy.
  
• Symptom management and prevention of complications in patients with severe oesophagitis, oesophageal stricture and oesophageal scleroderma. Higher PPI dose may be required for initial treatment.²¹
  
• Healing and prevention of relapse in patients with H. pylori-related peptic ulcer disease if eradication therapy fails or is contraindicated.²¹
  
• Prophylaxis in patients on long-term NSAIDs who are at high risk of NSAID-induced peptic ulceration.^11,21
  
• Symptom management, and healing and prevention of peptic ulcers in patients with Zollinger–Ellison Syndrome.^21,23 Higher PPI dose may be required for initial treatment.²³
  

Refer patients with complicated disease to a specialist.^11,21

Gastro-oesophageal reflux is a normal physiological occurrence and it is important to reassure patients that the occasional symptoms are not a cause for concern and may not necessarily need medicines.³ Reflux is considered pathological, and is classed as GORD, when it leads to symptoms sufficiently troublesome in severity or frequency to significantly impact the patient's quality of life.^3,11 Acid-suppressing medicines such as PPIs and H₂ antagonists, are effective for managing GORD, and relevant lifestyle measures should be suggested as adjunct therapy.^3,11,21

If reflux symptoms occur twice a week or more, or significantly impact the quality of life of the patient, start PPI therapy.^11,21

If symptoms are well controlled by initial PPI therapy, step down therapy.^3,11,21 Up to 30% of patients may be able to stop PPI therapy immediately after the initial course of therapy without experiencing symptoms.³ Discuss with the patient options available for stepping down and consider their preferences in developing the step-down plan.

Rebound acid hypersecretion is defined as an increase in gastric acid secretion above pre-treatment levels after acid suppression therapy, and may occur after stopping PPI therapy.^24,25 Symptomatic rebound acid hypersecretion entails difficult-to-manage gastro-oesophageal reflux symptoms and has been suggested as one of the factors contributing to the difficulty in discontinuing PPI therapy.²⁴

There are conflicting data on whether discontinuation of PPI therapy is associated with symptomatic rebound acid hypersecretion. Two systematic reviews found no strong evidence for symptomatic rebound acid hypersecretion in patients with acid–peptic disorders but acknowledged heterogeneity between studies and methodological weaknesses.^24,25 Some studies in healthy volunteers, particularly those who are negative for H. pylori infection,^26,27 have shown reflux-like symptoms after withdrawal from PPI therapy.^24,25

A step-down approach gradually reducing PPI dose before stopping, or using H₂ antagonists or antacids to manage symptoms, may help manage rebound acid hypersecretion.^19,24,25

When starting a patient with suspected GORD on PPI therapy, discuss upfront the anticipated duration of initial treatment and when they should return for review. Informing patients upfront that their dosage regimen may be adjusted at that stage will make for an easier conversation at review.

Advise patients on lifestyle modifications that may be helpful in reducing symptoms and the need for medicine. Also talk about medicines, both prescription and over the counter (OTC), which may exacerbate their symptoms.

Ask patients to return if symptoms persist or worsen while on PPI therapy, as further investigations may be needed.

If symptoms are well controlled after initial treatment, stepping down PPI therapy is recommended.^11,21 Because of the effectiveness of PPIs, some people may feel apprehensive about changes and anticipate the return of symptoms if the PPI is reduced or stopped. Reassure them by explaining the purpose of the step-down approach – to find the lowest dose of medicine that provides symptom relief and reduce the risk of adverse effects. Adverse effects and long-term safety of PPIs may be a greater concern to patients than health professionals realise.²⁸

Be clear about any prescribing changes you make, how they may alter the patient's experience and how to manage them. Depending on your choice of step-down approach, it may be useful to advise patients on the appropriate use of antacids or H₂ antagonists. Acknowledge that step-down therapy may need to be adjusted a few times for optimal symptom control and encourage regular reviews. While it is normal for symptoms to vary, remind the patient to get in contact if symptoms suddenly change.

Guidelines recommend trialling lifestyle measures as the first step or as adjunct therapy in managing symptoms of gastro-oesophageal reflux.^3,11,21 Certain foods, including spicy foods, citrus and carbonated beverages, as well as alcohol and tobacco are reported by many people to worsen reflux symptoms.²⁹ Fatty and late-evening meals, chocolate and caffeine are also reported as common precipitants.¹¹

Inform patients of these general suggestions but focus recommendations on identifying and avoiding their individual triggers while limiting unnecessary dietary restrictions.¹¹

Controlled weight loss is effective for improving symptoms in patients with GORD and should be routinely recommended to people who are overweight.^29-31 Elevating the bedhead can be helpful, particularly in patients with mostly night-time symptoms.^3,11,29

Some medicines may exacerbate reflux symptoms

Undertake regular medicine reviews and educate patients about medicines that may induce or exacerbate symptoms of reflux. Some medicines that cause or worsen symptoms of GORD are:^12,21,32

• anticholinergics
  
• barbiturates
  
• benzodiazepines
  
• beta-2 agonists
  
• bisphosphanates
  
• calcium channel blockers
  
• nitrates
  
• NSAIDs
  
• opioids
  
• theophylline.
  

Endoscopy is not a sensitive diagnostic test for GORD as about two-thirds of patients show no macroscopic evidence of oesophageal mucosal abnormalities.^3,11 Empirical therapy with a PPI is an efficient way to confirm diagnosis in most patients presenting with typical GORD symptoms such as heartburn and regurgitation.

While endoscopy is not recommended as a routine test for GORD, it has an important role in some clinical scenarios.^3,11,33

PPIs are generally considered safe and are well tolerated by most patients. The most common adverse effects include headache, nausea, vomiting and diarrhoea, which are reported to be in the order of 1–5%;^21,34 a rate little different from placebo.³⁴

Reports about more serious, albeit rare, adverse effects associated with PPI use, such as fractures, pneumonia, enteric infections and acute interstitial nephritis, have raised concerns. Most of the evidence for these adverse effects comes from observational studies. Although these studies are insufficient to establish a causal relationship, they may provide clues about possible associations and warrant consideration. As with any medicines, judicious prescribing will mitigate the risk of adverse events, particularly in patients more vulnerable to medicine-related adverse effects such as older people and those with comorbidities.

The absolute risk for fractures, pneumonia, enteric infections, and nutrient deficiencies is very low. Weigh the potential harms and benefits when prescribing a PPI and ensure patients are informed of the risks.^3,11

Bone fractures

Recent meta-analyses report a small increase in risk of hip and spine fractures associated with PPI use mostly in older people, but acknowledged the potential role of confounding factors.^35-37 Risk was present with both standard- and high-dose PPI,³⁵ and for duration of use both < 1 year and > 1 year.³⁶

PPI therapy appears to have little to no effect on bone mineral density,^38,39 suggesting any association between PPI use and fractures is not likely to be related to osteoporosis.

Pneumonia

• Small increase in the overall risk of pneumonia in PPI users in a meta-analysis of eight observational studies, although significant heterogeneity between studies was noted.⁴⁰ Similar findings reported by a meta-analysis evaluating community-acquired pneumonia in PPI users.⁴¹
  
• No association observed between PPI use and severe pneumonia requiring hospitalisation.^42,43
  

Enteric infections

• Increased susceptibilities to enteric infections caused by Salmonella, Campylobacter and Clostridium difficile have been reported.^44,45 Recent meta-analyses support a weak association between PPI therapy and C difficile infection but note significant heterogeneity.⁴⁶
  

Vitamin and mineral deficiencies

• PPI use has been associated with deficiencies in vitamin B12,⁴⁷ iron and magnesium.⁴⁸ In 2011, the TGA released a safety update acknowledging the potential association between prolonged use of a PPI and rare but serious hypomagnesaemia-related adverse events. They recommended prescribers be vigilant for PPI-associated hypomagnesaemia and noted that patients presenting with hypomagnesaemia may require PPI discontinuation.⁴⁹
  

Acute interstitial nephritis

Be alert to symptoms that may suggest interstitial nephritis in PPI users.⁵⁰ Consider risk for interstitial nephritis in PPI users with impaired renal function.³

• PPI use implicated as a cause of acute interstitial nephritis;^50-52 a 2007 systematic review concluded a low-prevalence association.⁵¹ These findings were supported by a recent case-controlled study of over half a million patients, which found a significantly increased risk of acute interstitial nephritis in current PPI users, compared with past users.⁵² Both studies noted a higher risk in older PPI users.^51,52

^a Lowest available dose of esomeprazole is 20 mg, 10 mg omeprazole is an appropriate step-down option.

Dr Christopher Pokorny, Gastroenterologist, Conjoint Associate Professor in the Faculty of Medicine, University of New South Wales, Sydney, NSW