Contents
Key Points
  • When starting a PPI for GORD explain that the expected duration of treatment is four to eight weeks
  • Review the need for ongoing use in all your patients receiving a PPI longer than eight weeks
  • Trial stepping down the dose and stopping therapy in patients with GORD whose symptoms are well controlled and taking a PPI for longer than eight weeks

Is your patient’s proton pump inhibitor still needed?

Proton pump inhibitors (PPIs) are among the most common medicines used in Australia.1 They are highly effective and when used in accordance with evidence-based guidelines are considered safe.2 When used for longer than recommended at high doses they are associated with adverse effects, especially in older patients.3-7

Older people make up the largest proportion of DVA patients dispensed PPI therapy; in 2013 PPIs were dispensed to over 70,000 DVA patients whose average age was 87 years.8

Many older people have a high prevalence of comorbidities which often means they take multiple medicines.9, 10 In addition to these comorbidities, DVA patients often have a number of health and wellbeing issues specific to them which increases the complexity of their care needs.11 Unnecessary medicine use further contributes to poor health outcomes and reduced quality of life.10, 12

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Review the need for ongoing PPI use

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Ask: Is a PPI still needed after eight weeks of treatment for GORD?

Patients with two or more episodes of gastro-oesophageal reflux symptoms per week or whose symptoms are severe enough to significantly impair quality of life are considered to have GORD.14 These patients often require a daily PPI at a standard dose for four to eight weeks before stepping down the dose and stopping (see Table 1).14, 16

Up to 30% of patients remain asymptomatic after stopping a PPI.14 GORD has a natural history of chronicity and relapse. Hence, a large proportion of patients have symptoms that recur from time to time and fluctuate in severity.9 Some patients might need intermittent therapy to control recurring symptoms.9

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Ask: Is the initial indication for PPI use still present?

If you do not know why your patient is using a PPI, check if they have had an endoscopy, hospitalisation for a bleeding ulcer, ongoing NSAID use, or have a history of heartburn or dyspepsia to help determine if stepping down the dose or stopping is appropriate.17 If the indication remains unknown, try stepping down to the lowest effective dose or stopping the PPI.17, 18

For information about diagnosing GORD, red flags that require investigation, or when to test for and treat Helicobacter pylori, go to ‘StePPIng the appropriate path with GORD medicines’ available at NPS MedicineWise: www.nps.org.au/news/stepping-the-appropriate-path-with-gord-medicines

Consider a Home Medicines Review (HMR) or a Residential Medication Management Review (RMMR). To find out more about the benefits of an HMR and the HMR process, refer to Not sure of the HMR process at: www.veteransmates.net.au/documents/10184/38810/Nov_2016_GP_Insert.pdf

A minority of patients might require ongoing PPI use including those with:17-20
  • Barrett’s oesophagus
  • severe oesophagitis
  • a history of GI bleeding or those at high risk of a GI bleed who have not had a previous bleed
  • long-term NSAID use in those at risk of NSAID-induced peptic or gastric ulceration
  • Zollinger-Ellison syndrome
  • oesophageal scleroderma
  • oesophageal stricture.

In this select group of patients consider referring to a gastroenterologist for consultation, if you are considering trialling a reduction in dose or require advice about ongoing PPI use.

Step-down the dose or stop the PPI

table table
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Trial stepping down to the lowest effective dose and stopping the PPI
  • If your patient has uncomplicated GORD and symptoms are well controlled after a maximum of eight weeks.14, 17, 18 A previous Veterans’ MATES topic targeting PPI use found that over half of respondents did not realise they could reduce their PPI dose.21
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If symptoms are not well controlled after eight weeks, confirm optimal PPI use
  • confirm compliance,14
  • review medicines that might be:
    • causing or worsening symptoms including NSAIDs, bisphosphonates, tetracyclines, nitrates or calcium channel blockers and change or cease where appropriate.9
    • impairing the effect of the PPI including rifampicin or enzalutamide and increase the dose of the PPI accordingly.9
  • If compliance is satisfactory, consider:
    • endoscopy if the diagnosis is unclear, your patient complains of difficulty or pain when swallowing, or complications are suspected.14 If no other cause is evident, consider continuing the same PPI at the previous dose,18 or at a high dose for a further four to eight weeks.9, 14 A standard dose given twice a day is more effective than a double dose given once a day. Then step-down to the lowest effective dose and stop. If symptoms persist, consider other diagnoses, for example functional dyspepsia,14 peptic ulcer9 or testing for Helicobacter pylori.17
    • referral for specialist advice if symptoms persist and diagnosis still remains unclear.9
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Step-down and stop the PPI

If your patient has:

  • been treated for peptic ulcer disease caused by use of NSAIDs, symptoms are now well controlled and the patient has ceased their NSAIDs
  • upper GI symptoms without endoscopy and symptoms are well controlled
  • continued a PPI for stress ulcer prophylaxis treatment after discharge from an intensive care setting
  • been treated for Helicobacter pylori and is now asymptomatic.17
Why stepping down the dose is most effective
  • Stopping a PPI abruptly can result in rebound symptoms in some patients.14 If you are stopping the PPI abruptly, consider a regular or ‘as needed’ H2-receptor antagonist or an antacid until symptoms are controlled.14
  • Stepping down the dose appears to be the most effective way to avoid rebound symptoms.14, 22 Individualise the dose and taper slowly before stopping. Advise your patients to return for review if their symptoms recur and their quality of life is reduced.14
  • As a general guide, step-down the dose by half each time or give a dose on alternate days.14
  • If symptoms are not adequately controlled on the step-down dose, recommence the lowest effective dose and frequency of PPI until symptoms are controlled.14, 18 If symptoms are unmanageable, consider referral to a gastroenterologist for expert advice.14
  • Explain to your patients that their symptoms might vary from time to time because of changes in their diet, weight, smoking or stress levels and that they might need to take a PPI on days when symptoms occur.14
  • Evidence suggests oesophageal sensitivity or an altered perception in the oesophagus plays a significant role in generating reflux symptoms in some patients. Stress, anxiety and reduced quality of life is thought to play a part in increasing the perception of reflux symptoms in some patients with no obvious features of the disease.23, 24

Managing anxiety-related conditions might be helpful in reducing reflux symptoms in these patients. DVA can pay for treatment for any mental health condition without the need for the condition to be accepted as related to service. This is known as non-liability health care. For further information contact DVA on 1800 VETERAN (1800 838 372) or visit: www.dva.gov.au/nlhc

Follow-up after stopping PPI use

Ask your patient to make an appointment four weeks after stopping their PPI.17 At that appointment keep encouraging your patient to:

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Adhere to diet and lifestyle modifications that are effective

Highlight to your patient that losing weight if they are overweight and stopping smoking if they smoke can help to reduce symptoms.25 Evidence to support reduction of weight or waist circumference, especially in obese people, and smoking cessation is significant.25-27

Dietician, physiotherapy and exercise physiology services are available to eligible DVA patients which might help support patients to make these changes. For further information visit: www.dva.gov.au/providers/allied-health-professionals

Eligible DVA patients have access to medicines for nicotine dependence. Encourage contact with the national smoking Quitline on 13 7848 or at: www.quitnow.gov.au

Raising the head of the bed can help reduce symptoms if they are worse at night or disturb sleep.26 Adjustable bed heads and bed blocks can be provided to eligible DVA patients through the ‘Rehabilitation Appliances Program (RAP) National Schedule of Equipment’ at: www.dva.gov.au/health-and-treatment/care-home-or-aged-care/equipment-and-modifications-you-and-your-home

Evidence for the effectiveness of other lifestyle and dietary modifications is limited.9 Advise your patients to continue dietary changes only if they are effective, to avoid unnecessary food restrictions.14

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Manage occasional symptoms

Explain to your patient that occasional symptoms can often be managed with the use of a PPI when needed.14 Alternatively, intermittent use of an alginate/antacid combination, an antacid or a H2-receptor antagonist might be all that is needed to control occasional symptoms.14 Antacids, for example magnesium hydroxide plus aluminium hydroxide, and calcium carbonate plus glycine, are available on the PBS.9 Alginate/antacid-based formulations, for example sodium alginate plus calcium carbonate and sodium bicarbonate, are available over-the-counter.

If your patient is taking an antacid or an alginate/antacid-based formulation, explain that the liquid form is more effective than the tablet form.14

You can access medicines for treatment of acid-related disorders, peptic ulcer and GORD on the PBS at: www.pbs.gov.au/browse/body-system?depth=3&codes=a02b#a02b

An update on adverse effects associated with PPI use

Evidence from observational studies suggests there is an association between PPI use and an increased risk of adverse effects, especially with long-term use.

Hip fracture

Results of studies investigating an association between PPI use and fracture have been inconsistent. More recent meta-analyses and an overview of systematic reviews indicate PPI use modestly increases the risk of fracture at the hip, spine and any other site after falling.5, 28, 29 H2-receptor antagonists do not appear to be associated with an increased fracture risk.29

Kidney disease

A large prospective cohort study found for every 25 patients treated with a PPI, there would be 1 extra case of chronic kidney disease than if they were not treated.30 Twice daily dosing appeared to be associated with a higher risk compared to once daily dosing.30 A large population-based study of more than 290,000 participants found for every 187 older patients treated with a PPI, there would be 1 extra case of acute kidney injury including interstitial nephritis, than if they were not treated.3

Clostridium difficile infection

A meta-analysis of studies found for every 67 patients treated with a PPI, there would be 1 extra case of Clostridium difficile infection than if they were not treated. For every 121 patients treated with a H2-receptor antagonist, there would be 1 extra case of Clostridium difficile infection.31 Gut microbiota and gastric acidity play key roles in maintaining healthy and balanced immune and inflammatory processes.32, 33 Overuse of PPIs can lead to a significant shift in gastric and intestinal microbial composition and stomach pH, which is thought to predispose patients to debilitating infections, including Clostridium difficile-associated diarrhoea, Salmonella and Campylobacter infections.31, 32, 34-36

Vitamin B12 deficiency

Several studies suggest there is an association between PPI use and an increased risk of vitamin B12 deficiency.37 Older patients are already at an increased risk of vitamin B12 deficiency due to impaired absorption, and use of other prescribed medicines, e.g. metformin.37

Pneumonia

Several studies suggest an association between PPI use and pneumonia exists.6, 7, 38 A large study of DVA patients aged 65 years and over found for every 80 patients treated with a PPI, there would be 1 extra patient hospitalised for pneumonia than if they were not treated with a PPI.7

Hypomagnesaemia

In 2011, the Therapeutic Goods Administration warned of a potential association between prolonged PPI use and hypomagnesaemia-related adverse events including tetany, seizures, delirium and cardiac arrhythmias.39 While it was reported these events occurred rarely, there was no reliable way to predict which patients might be at risk but that some medicines, including loop and thiazide diuretics, might cause or worsen hypomagnesaemia.39

Other new research

There does not appear to be any association between long-term PPI use and the development of gastric cancer.19, 40 A systematic review of patients using PPIs for longer than three years found an increased prevalence of gastric hyperplasia and raised gastrin levels. Helicobacter pylori-positive patients had a higher risk of developing hyperplasia compared with Helicobacter pylori-negative patients, but no cancers were found in any of the studies explored.40

Footnote: A Hong Kong study showed long-term PPI use was associated with an increased risk of gastric cancer in Helicobacter pylori-positive patients who had received eradication therapy. Patients taking a daily PPI for three or more years were at the highest risk. It is important to note that the Helicobacter Pylori species found in Hong Kong are more virulent when compared to those usually found in Australia and to date this finding has not been shown in an Australian patient cohort.41

References

  1. Department of Health. Top 10 drugs 2016-17. Australian Prescriber. 2017; 40(6): 237.
  2. Hughes J, Tanpurekul W, Keen N, Ee H. Reducing the cost of proton pump inhibitors by adopting best practice. Quality in Primary Care. 2009; 17(1): 15-21.
  3. Antoniou T et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open. 2015; 3(2): E166-71.
  4. Cheungpasitporn W et al. Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies. Ren Fail. 2015; 37(7): 1237-41.
  5. Zhou B, Huang Y, Li H, Sun W, Liu J. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int. 2016; 27: 339-47.
  6. Eom C et al. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis CMAJ. 2011; 183(3): 310-319.
  7. Ramsay E, Pratt N, Ryan P, Roughead E. Proton pump inhibitors and the risk of pneumonia: a comparison of cohort and self-controlled case series designs. BMC Medical Research Methodology. 2013; 13: 82.
  8. Pratt N et al. Use of proton pump inhibitors among older Australians: national quality improvement programmes have led to sustained practice change. Int J Qual Health Care. 2017; 29(1): 75-82.
  9. Australian Medicines Handbook. Adelaide. Australian Medicines Handbook Pty Ltd. 2018.
  10. Hilmer S. The dilemma of polypharmacy. Australian Prescriber. 2008; 31: 2-3.
  11. Australian Government Department of Veterans' Affairs. Canberra. Social Health Strategy 2015-2023 for the Veteran and Ex-service Community. 2015.
  12. Maher R, Hanlon J, Hajjar E. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014; 13(1): 57-65.
  13. Gadzhanova S, Roughead E, Mackson J. Initiation and duration of proton pump inhibitors in the Australian veteran population. Intern Med J. 2010; 42: e68-73.
  14. Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited. March 2018. Available at: http://online.tg.org.au/ip/desktop/index.htm [Accessed May 2018].
  15. Choosing Wisely Australia. An initiative of NPS MedicineWise. 2015. Recommendations: Gastroenterological Society of Australia and the Royal Australian College of General Practitioners: tests, treatments and procedures for healthcare providers and consumers to question. Available at: www.choosingwisely.org.au/recommendations/racgp [Accessed March 2018].
  16. NPS MedicineWise, Choosing Wisely Australia: Proton pump inhibitors: too much of a good thing? Available at: www.nps.org.au/medical-info/clinical-topics/news/proton-pump-inhibitors-too-much-of-a-good-thing [Accessed April 2018].
  17. Choosing Wisely Canada. Bye-bye, PPI: a toolkit for deprescribing proton pump inhibitors in EMR-enabled primary care settings. 2017. Available at: https://choosingwiselycanada.org/perspective/ppi-toolkit/ [Accessed May 2018].
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  20. Keung C, Hebbard G. The management of gastro-oesophageal reflux disease. Australian Prescriber. 2016; 39(1): 6-10.
  21. Australian Government Department of Veterans' Affairs Health Claims Database, University of South Australia, QUMPRC. [Accessed April 2018].
  22. Haastrup P, Paulsen M, Begtrup L, Hansen J, Jarbol D. Strategies for discontinuation of proton pump inhibitors: a systematic review. Fam Pract. 2014; 31(6): 625-30.
  23. Yadlapati R, Tye M, Keefer L, Kahrilas P, Pandolfino J. Psychosocial distress and quality of life impairment are associated with symptom severity in PPI non-responders with normal impedance-pH profiles. Am J Gastroenterol. 2018; 113: 31-38.
  24. Koop H. Medical therapy of gastroesophageal reflux disease beyond proton pump inhibitors: where are we heading? Visceral Medicine. 2018; 34: 110-115.
  25. Kang J, Kang J. Lifestyle measures in the management of gastro-oesophageal reflux disease: clinical and pathophysiological considerations. Ther Adv Chronic Dis. 2015; 6(2): 51-64.
  26. Ness-Jensen E, Hveem K, El-Serag H, Lagergren J. Lifestyle intervention in gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2016; 14(2): 175-82 e1-3.
  27. Park S et al. Weight loss and waist reduction is associated with improvement in gastroesophageal disease reflux symptoms: a longitudinal study of 15 295 subjects undergoing health checkups. Neurogastroenterol Motil. 2017; 29: 1-7.
  28. Abramowitz J et al. Adverse event reporting for proton pump inhibitor therapy: an overview of systematic reviews. Otolaryngol Head Neck Surg. 2016; 155(4): 547-54.
  29. Yu E, Bauer S, Bain P, Bauer D. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med. 2011; 124(6): 519-26.
  30. Lazarus B et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016; 176(2): 238-46.
  31. Kwok C et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012; 107: 1011-9.
  32. Minalyan A, Gabrielyan L, Scott D, Jacobs J, Pisegna J. The gastric and intestinal microbiome: role of proton pump inhibitors. Curr Gastroenterol Rep. 2017; 19: 2-10.
  33. Gallo A, Passaro G, Gasbarrini A, Landolfi R, Montalto M. Modulation of microbiota as treatment for intestinal inflammatory disorders: an uptodate. World J Gastroenterol. 2016; 22(32): 7186-202.
  34. Maier L et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018; 555: 623-628.
  35. Jackson M et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016; 65: 749-56.
  36. Imhann F et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016; 65: 740-8.
  37. Maes M, Fixen D, Linnebur S. Adverse effects of proton-pump inhibitor use in older adults: a review of the evidence. Ther Adv Drug Saf. 2017; 8: 273-297.
  38. Zirk-Sadowski J et al. Proton-pump inhibitors and long-term risk of community-acquired pneumonia in older adults. J Am Geriatr Soc. 2018: April 20. doi: 10.1111/jgs.15385 [Epub ahead of print].
  39. Australian Government.Therapeutic Goods Administration. Medicines Safety Update: risk of hypomagnesaemia with proton pump inhibitors. Australian Prescriber. 2011; 34(3): 81.
  40. Lundell L, Vieth M, Gibson F, Nagy P, Kahrilas P. Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology. Aliment Pharmacol Ther. 2015; 42: 649-63.
  41. Cheung K et al. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut. 2018; 67: 28-35.

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Contents
Key Points
  • When starting a PPI for GORD explain that the expected duration of treatment is four to eight weeks
  • Review the need for ongoing use in all your patients receiving a PPI longer than eight weeks
  • Trial stepping down the dose and stopping therapy in patients with GORD whose symptoms are well controlled and taking a PPI for longer than eight weeks