Oral proton pump inhibitors (PPIs)

Treatment Guideline Oral proton pump inhibitors (PPIs) Introduction The high efficacy and low toxicity of proton pump inhibitors (PPIs) has contributed to their frequent prescription worldwide, often without clear indication. Such widespread over-prescription incurs avoidable financial and clinical costs 1. PPI use is associated with a number of adverse consequences including Clostridium difficile infection, community acquired pneumonia, osteoporosis, hypomagnesaemia and kidney injury 2-7. In light of this, PPI prescription should be reserved for patients where there is a clear indication and clinicians should consider stopping PPIs when the indication is unclear. There are data to support stopping PPIs in patients who have been taking them long term 8. Preliminary points: 1. Use oral PPIs as first line 2. If the oral route is compromised (e.g. by vomiting, low GCS) then consider using: First line: lansoprazole orodispersible tablet orally or via nasogastric tube, or oral PPI with anti-emetic Second line: IV PPI bolus 3. When stopping PPI therapy, patients may experience a rebound increase in dyspepsia in the short term and therefore should be advised to use antacids (e.g. Peptac ) as required 4. The PPI dosing categories are referenced in guideline (table 1) 9 : Table 1 - PPI doses PPI Full dose Low dose (on-demand dose) Double dose Esomeprazole 20 mg once a day Not available 40 mg once a day Lansoprazole 30 mg once a day 15 mg once a day 30 mg twice a day Omeprazole 20 mg once a day 10 mg once a day 40 mg once a day Pantoprazole 40 mg once a day 20 mg once a day 40 mg twice a day Rabeprazole 20 mg once a day 10 mg once a day 20 mg twice a day Review date: November 2020 Page 1 of 8

Indications for prescribing PPIs in Secondary Care: 1. Patients admitted with suspected upper GI bleeding Discontinue contributory medications where possible on a risk versus benefit basis PPIs should not be used prior to endoscopic diagnosis in patients presenting with acute upper gastrointestinal bleeding 10-11 2. Peptic ulcer (gastric or duodenal) 9 If taking Non-steroidal anti-inflammatory drugs (NSAIDs): Stop NSAIDs where possible Offer a double-dose PPI (or histamine-2 receptor anatagonist (H2RA)) therapy for 8 weeks Offer H.pylori eradication therapy to people who have tested positive for H.pylori and who have peptic ulcer disease. If not taking NSAIDs Offer a double-dose PPI or H2RA for 4 to 8 weeks Offer H.pylori eradication therapy to people who have tested positive for H.pylori and who have peptic ulcer disease. 3. Mild gastro-oesophageal reflux disease (GORD) 9 Offer a full-dose PPI for 4 to 8 weeks If symptoms recur after initial treatment, offer a PPI at the lowest dose necessary to control symptoms and consider an 'as required' dosing approach Offer H2RA therapy if there is an inadequate response to PPIs 4. Moderate-severe GORD (LA grade C and D) 12 Use esomeprazole 40mg once daily for 4 to 8 weeks, then continue long-term 20mg once daily 5. Barrett s oesophagus 13 Use of full-dose PPI is recommended for symptom control In asymptomatic patients with Barrett's oesophagus there is insufficient evidence to recommend routine PPI use Review date: November 2020 Page 2 of 8

6. Dyspepsia 9 Discontinue contributory medications where possible Offer empirical full-dose PPI for 4 weeks If symptoms recur after the initial PPI course then recommence the PPI at the lowest dose necessary to control symptoms and consider 'as required' dosing Offer H2RA therapy if there is an inadequate response to a PPI 7. Functional dyspepsia 9 Offer H. pylori 'test and treat' If H.pylori has been excluded and symptoms persist offer either a low-dose PPI or H2RA for 4 weeks If symptoms persist offer a PPI or H2RA at the lowest dose necessary to control symptoms and consider 'as required' dosing Avoid long-term, frequent dose, continuous antacid therapy (it only relieves symptoms in the short term rather than preventing them) 8. Use of PPIs for gastro-protection NSAIDs 14 Co-prescribe a PPI at full-dose in patients commencing NSAIDs who: 1. Develop dyspepsia 2. Have one or more risk factors: o History of gastrointestinal bleeding, peptic ulcer or gastroduodenal perforation o Aged 65 years or older o Using maximum recommended NSAID dose o Concomitant use of drugs known to increase the risk of gastrointestinal bleeding /dyspepsia (e.g. anticoagulants, aspirin, corticosteroids, antidepressants (selective serotonin reuptake inhibitors, venlafaxine or duloxetine)) o Significant co-morbidity (e.g. diabetes, renal/hepatic impairment, cardiovascular disease, advanced cancer or hypertension) o Anticipated prolonged NSAIDs use, including patients with: Rheumatoid arthritis or osteoarthritis Chronic back pain if over 45 years old Review date: November 2020 Page 3 of 8

Corticosteroids 15-16 There is no high quality evidence to suggest that corticosteroids cause GI ulceration, although they do cause dyspepsia and may be associated with an increased risk of gastrointestinal bleeding or perforation in hospitalised patients Consider co-prescribing a PPI at full-dose whilst the patient is taking corticosteroids if: 1. The patient develops dyspepsia 2. There are one or more risk factors for GI bleeding including: o History of gastrointestinal bleeding, peptic ulcer or gastroduodenal perforation o Aged 65 years or over o Concomitant use of drugs known to increase the risk of gastrointestinal bleeding/dyspepsia (e.g. anticoagulants, aspirin, NSAIDs, antidepressants (selective serotonin reuptake inhibitors, venlafaxine or duloxetine)) o Significant co-morbidity (e.g. advanced cancer) Stress ulcer prophylaxis on the Intensive Care Unit (ICU) 17-19 Aim to commence early enteric feeding The evidence for stress ulcer prophylaxis in critically ill patients is extremely weak and mostly observational with several studies suggesting harm predominantly ventilator associated pneumonia. There is also limited evidence for the drug choice in these cases. On this basis, local practice is to only give acid-suppression therapy in patients who are not being enterally-fed on a case by case basis. A full dose PPI or H2RA may be used. Consider risk factors such as: o Respiratory failure o Coagulopathy o Sepsis o Severe hypotension o Renal failure o History of gastrointestinal ulcer or bleed within 1 year of admission o Hepatic failure o Major trauma o Burns o Spinal cord injury o Organ transplantation o GCS <11 o Surgery o Concomitant use of medications that are known to increase the risk of gastrointestinal bleeding/dyspepsia (e.g. anticoagulants, aspirin, NSAIDs, corticosteroids, antidepressants (selective serotonin reuptake inhibitors, venlafaxine or duloxetine)) o ICU stay of at least 6 days In patients who are receiving enteral feed only use acid-suppression in patients taking pre-existing acidsuppressing medications or where there is concern about GI bleeding. If prophylaxis commenced, review on-going need once high risk factors are resolved or transferred from ICU Review date: November 2020 Page 4 of 8

9. Oesophagitis 9 Mild/Moderate: Severe: Offer a full dose PPI for 4 to 8 weeks, then: o If clinical improvement has occurred then reduce the PPI dose to the lowest necessary to control symptoms and consider an 'as required' dosing approach o If there has been no clinical improvement then escalate PPI therapy to a double dose regimen or consider switching to an alternative PPI or H2RA Please note specific PPI dosing for severe oesophagitis from table 2 (below) Offer full dose PPI for 8 weeks for healing and then: o If healing has been achieved then continue the full dose as long-term maintenance therapy taking into account patient preferences and tolerability o If healing is not achieved then consider escalating therapy to a double dose of the initial PPI or switching to an alternative PPI at full or double dose Table 2: PPI dosing for severe oesophagitis PPI Full dose Low dose (on-demand dose) Double dose Esomeprazole 40 mg once a day 20 mg once a day 40 mg twice a day Lansoprazole 30 mg once a day 15 mg once a day 30 mg twice a day Omeprazole 40 mg once a day 20 mg once a day 40 mg twice a day Pantoprazole 40 mg once a day 20 mg once a day 40 mg twice a day Rabeprazole 20 mg once a day 10 mg once a day 20 mg twice a day Review date: November 2020 Page 5 of 8

10. PPI prescribing - caveats Clopidogrel 20 Concomitant use of clopidogrel with omeprazole or esomeprazole is not recommended Current available data does not support nor completely exclude a potential interaction between clopidogrel and alternative PPIs. The potential risk of a reduction in efficacy of clopidogrel should be weighed against the potential benefit of the PPI Hypomagnesaemia 6 Severe hypomagnesaemia has been reported infrequently in patients treated with PPIs although the exact incidence is unknown In some cases hypomagnesaemia occurred after 3 months of PPI therapy, but most occurred after 1 year of treatment In most case reports, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI Consider optimising magnesium levels before starting treatment and periodically during prolonged treatment, especially in those taking digoxin or other drugs that can cause hypomagnesaemia (e.g. diuretics) PPIs must only be commenced and continued with a clear indication and their ongoing use regularly reviewed Community acquired pneumonia 5.21 Some observational studies and meta-analyses suggest that PPIs may be associated with an increased risk of community-acquired pneumonia, particularly within the first 30 days of PPI use, however these studies are confounded by bias and reflux disease and so no firm conclusions can be drawn PPIs must only be commenced and continued with a clear indication and their ongoing use regularly reviewed Clostridium difficile infection (CDI) 22 Public Health England guidelines recommend considering stopping PPIs and H2RA in patients with or at high risk of CDI Given the extent of PPI prescribing, the number of potentially avoidable CDI cases could be significant The challenge presented by CDI, the evidence of an association with PPI use, and current concerns about overuse of PPIs, provide good reasons to critically review PPI and H2RA prescribing Osteoporosis 3.23 Observational studies suggest there may be a modest increase in the risk of hip, wrist or spinal fracture with PPIs especially if used in high doses and for prolonged durations (>1 year). The increased risk was observed mainly in elderly patients but confounding factors may have contributed Review date: November 2020 Page 6 of 8

Bone health should be optimised according to current guidelines and PPIs must be commenced and continued only with a clear indication Kidney injury Acute 7 PPI use may rarely cause acute interstitial nephritis (AIN) Ongoing PPI use should be reviewed if an acute kidney injury (AKI) develops following the recent prescription of a PPI or if AIN develops following acute or chronic use Current evidence does not recommend withholding PPI in all cases of AKI regardless of cause 4, 24-25 Chronic Although studies indicate that long-term PPI use is associated with a higher risk of CKD findings may be confounded by other factors such as NSAID use and hence there is a need for further investigation PPIs must be commenced and continued only with a clear indication and their ongoing use regularly reviewed References: 1. Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ Br Med J. 2008;336(7634):2 3. 2. Dial S, Delaney JAC, Barkun A, Suissa S. Use of Gastric Acid Suppressive Agents and the Risk of Community-Acquired Clostridium difficile Associated Disease. JAMA. 2005;294(23):2989 95. 3. Khalili H, Huang ES, Jacobson BC, Jr CAC, Feskanich D, Chan AT. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors : a prospective cohort study. Br Med J. 2012;372(January):1 13. 4. Arora P, Gupta A, Golzy M, Patel N, Carter RL, Jalal K, et al. Proton pump inhibitors are associated with increased risk of development of chronic kidney disease. BMC Nephrol [Internet]. 2016;17(1):112. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27487959%5cnhttp://www.pubmedcentral.nih.gov/articlerender.f cgi?artid=pmc4973085 5. Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: A systematic review and meta-analysis. PLoS One. 2015;10(6):1 18. 6. Proton pump inhibitors in long-term use: reports of hypomagnesaemia. Medicines and Healthcare Products Regulatory Agency. Drug Saf Updat. 2012;5(9):A1. 7. Sampathkumar K, Ramalingam R, Prabakar A, Abraham A. Acute interstitial nephritis due to proton pump inhibitors. Indian J Nephrol. 2013;23(4):304 7. 8. Björnsson E, Abrahamsson H, Simrén M, Mattsson N, Jensen C, Agerforz P, et al. Discontinuation of proton pump inhibitors in patients on long-term therapy: A double-blind, placebo-controlled trial. Aliment Pharmacol Ther. 2006;24(6):945 54. 9. NICE. Gastro-oesophageal reflux disease and dyspepsia in adults : investigation and management NICECG184. 2014; 10. Scottish Intercollegiate Guidelines Network. Management of Acute Upper and Lower Gastrointestinal Bleeding - A National Clinical Guideline. Scottish Intercoll Guidel Netw [Internet]. 2008;(September):1 56. Review date: November 2020 Page 7 of 8

Available from: http://www.sign.ac.uk/guidelines/fulltext/105/index.html 11. NICE. Acute upper gastrointestinal bleeding, NICE CG141. 2012. 12. Schmitt C, Lightdale C, Hwang C, Hamelin B. A multicenter, randomized, double-blind, 8-week comparative trial of standard doses of esomeprazole (40 mg) and omeprazole (20 mg) for the treatment of erosive esophagitis. Dig Dis Sci. 2006;51(5):844 50. 13. Fitzgerald RC, di Pietro M, Ragunath K, Ang Y, Kang J-Y, Watson P, et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett s oesophagus. Gut [Internet]. 2014;63(1):7 42. Available from: http://gut.bmj.com/lookup/doi/10.1136/gutjnl-2013-305372 14. NICE. NICE Clinical Knowledge Summary (last revised July 2015); Scenario: NSAID s prescribing issues [Internet]. [cited 2017 May 25]. Available from: https://cks.nice.org.uk/nsaids-prescribingissues#!scenarioclarification:1 15. NICE. NICE Clinical Knowledge Summary - Corticosteroids - Oral [Internet]. NICE Clinical Knowledge Summary. 2015 [cited 2017 May 25]. Available from: https://cks.nice.org.uk/corticosteroids-oral#!scenario 16. Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open [Internet]. 2014;4(5):e004587. Available from: http://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2013-004587 17. Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton-pump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol [Internet]. 2012;5(4):219 32. Available from: http://tag.sagepub.com/cgi/doi/10.1177/1756283x12437358 18. Alhazzani W, Alenezi F, Jaeschke R, Moayyedi P, Cook D. Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and metaanalysis. Crit Care Med. 2013;41(3):693 705. 19. Lin P, Chang C, Hsu P, Tseng P, Huang Y. The efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta-analysis. Crit Care Med. 2010;38(4):1197 205. 20. Clopidogrel and proton pump inhibitors: interaction updated advice. Medicines and Healthcare Products Regulatory Agency [Internet]. Vol. 3, Drug Safety Update. 2010. Available from: https://www.gov.uk/drugsafety-update/clopidogrel-and-proton-pump-inhibitors-interaction-updated-advice 21. Filion KB, Chateau D, Targownik LE, Gershon A, Durand M, Tamim H, et al. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: Replicated cohort studies with meta-analysis. Gut [Internet]. 2014;63(4):552 8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3963530&tool=pmcentrez&rendertype=abstr act 22. UK Medicines Information (UKMI) (2015); Medicines Q&A s Clostridium difficile infection is use of proton pump inhibitors a risk factor? [Internet]. [cited 2017 Apr 25]. Available from: https://www.sps.nhs.uk/wp-content/uploads/2016/02/nw-qa244.3-c-difficile-and-ppis-.pdf 23. Drug Safety Update April 2012, vol 5 issue 9: A2 [Internet]. [cited 2017 Apr 25]. Available from: https://www.gov.uk/drug-safety-update/proton-pump-inhibitors-in-long-term-use-increased-risk-offracture#fnref:2 24. Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int [Internet]. 2016; Available from: http://dx.doi.org/10.1016/j.kint.2016.12.021 25. Perazella DGMMA. PPIs and kidney disease: from AIN to CKD. J Nephrol. 2016;29(5):611 6. Review date: November 2020 Page 8 of 8