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• W4385477674 abstract "Opening Vignette Madam Tan, a 62-year-old retired accountant, was on a follow-up visit for type 2 diabetes mellitus, hypertension, dyslipidaemia and ischaemic heart disease. Her active medications included metformin, amlodipine, simvastatin and aspirin. She visited your practice 4 weeks ago for dyspepsia, and you prescribed omeprazole 40 mg every morning (OM). As her symptoms did not improve, she was admitted to hospital for further evaluation. She underwent oesophagogastroduodenoscopy, which showed antral gastritis. There were no focal ulcers or suspicious lesions, and rapid urease test for Helicobacter pylori infection was negative. She was diagnosed with functional dyspepsia and discharged after her symptoms improved. She has remained on omeprazole 40 mg OM and is under review at your clinic. She would like to know if she should continue taking omeprazole.WHAT ARE PROTON PUMP INHIBITORS? Proton pump inhibitors (PPIs) reduce acid secretion by irreversibly binding to gastric H+K+ ATPase proton pumps located along the apical border of gastric parietal cells. The half-life of PPIs is short, but new proton pumps must be synthesised for gastric acid secretion to be restored. Examples of commonly prescribed PPIs include omeprazole, esomeprazole, dexlansoprazole, rabeprazole and pantoprazole. Standard doses are shown in Table 1.Table 1: Standard doses for commonly prescribed proton pump inhibitors.HOW COMMONLY PRESCRIBED ARE PROTON PUMP INHIBITORS? Proton pump inhibitors are one of the most prescribed drugs. A clinical record review of 150 consecutive patients aged ≥65 years admitted to Internal Medicine in National University Hospital, Singapore, reported that 80 patients (64 existing, 16 new) had a prescription for PPIs on discharge. The review aimed to evaluate the indications for PPI prescription, and the authors concluded that PPIs are commonly prescribed without documentation of valid indications. In Changi General Hospital, Singapore, approximately 160,000 patients received 650,000 prescriptions for PPIs between 2013 and 2016. A Spanish drug utilisation study reported that 54.75% of patients admitted were prescribed a PPI on discharge. Notably, 80.24% of these patients were reported to have incorrect indications for PPIs.[1] WHAT ARE THE POTENTIAL SIDE EFFECTS OF PROTON PUMP INHIBITORS? There is increasing evidence of associations between PPI use and various adverse clinical events. These include the development of kidney disease, vitamin B12 deficiency, hypomagnesaemia, fractures, dementia and cardiovascular events. Patients are also postulated to be at an increased risk of infective complications, with pneumonia and Clostridium difficile infection (CDI) being the most reported. Further information can be obtained from the American Gastroenterological Association Clinical Practice Update published in 2017.[2] Kidney disease Case reports and retrospective observational studies have linked PPIs to acute interstitial nephritis, acute kidney injury and chronic kidney disease. One study evaluated patients newly initiated on PPIs (n = 125,596) in comparison to patients initiated on histamine H2 receptor antagonists (n = 18,436) for acid suppression over a 5-year period.[3] The cohort comprised mostly older white male US veterans, and the PPI users in the cohort were found to have an increased risk of estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 (hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.15–1.24) and their eGFR declined above 50% from baseline (HR 1.30, 95% CI 1.15–1.48) in the absence of intervening acute kidney injury. Overall, based on available evidence and the inherent limitations in study designs, no causality has been established.[2] Vitamin B12 deficiency Pepsin is active only when gastric pH is <4. It is required as a catalysing enzyme to facilitate binding of vitamin B12 to intrinsic factor. Long-term PPI use and higher gastric pH are postulated to impair absorption of vitamin B12. Conflicting results have been published on the association of PPI use and vitamin B12 deficiency, and further prospective studies that are specifically designed to evaluate this association are needed. There are no specific recommendations for monitoring serum vitamin B12 levels in patients on long-term PPIs. Hypomagnesaemia The first case of severe hypomagnesaemia occurring after PPI use was described in 2006. Subsequently, some case–control and cross-sectional studies found an association between PPI use and hypomagnesaemia, although others have found no association.[4] A meta-analysis (a total of 16 studies, 131,507 patients) aimed at evaluating the association between PPI use and the incidence and prevalence of hypomagnesaemia was published in 2019.[5] The use of PPI was found to be significantly associated with hypomagnesaemia, with a pooled adjusted odds ratio (OR) of 1.71 (95% CI 1.33–2.19). Subgroup analyses also showed that high-dose PPI was associated with higher odds of hypomagnesaemia relative to standard dose PPI use (pooled adjusted OR 2.13, 95% CI 1.26–3.59). Hypomagnesaemia appears to occur after prolonged PPI use (at least 3 months). The underlying mechanism is not completely understood, but appears to be due to impaired gastrointestinal absorption. Since not all patients on prolonged courses of PPI develop hypomagnesaemia, this may be an idiosyncratic reaction with potential genetic predispositions. The US Food and Drug Administration recommends obtaining magnesium levels at treatment onset, especially if patients are expected to be on PPI for prolonged periods of time. Follow-up should also be considered if the patient has the risk factors for hypomagnesaemia, including age >65 years, diabetes mellitus, advanced kidney disease, and concomitant use of hypomagnesaemia-inducing drugs or drugs potentially affected by serum magnesium levels, such as diuretics. Bone fractures The evidence behind the postulated association of PPIs with fractures is largely from observational studies, with the underlying mechanism unknown and the causality yet to be proven. A meta-analysis (a total of 18 studies, 244,109 fracture cases) aimed at evaluating the association of PPI with fracture risk was published in 2016. Pooled analysis reported that PPI use was found to moderately increase the risk of hip fracture (relative risk 1.27, 95% CI 1.16–1.36).[6] While some studies suggest that PPIs impair osteoclastic activity and bone remodelling, there is insufficient evidence to recommend calcium supplementation or regular bone mineral density monitoring. Dementia The possible association between long-term PPI use and dementia was first identified by a multicentre cohort German study published in 2015, in which patients receiving PPIs were reported to have a significantly increased risk of dementia and Alzheimer’s disease (HR 1.38, 95% CI 1.04–1.83 and HR 1.44, 95% CI 1.01–2.06, respectively). It was postulated that PPIs may increase the accumulation of amyloid beta peptide levels, a major pathological marker for dementia in Alzheimer’s disease, as well as inhibit degradation of amyloid beta peptides by lysosomes. A recently published systematic review and meta-analysis of all available observational studies (a total of 11 studies, 642,949 subjects) found no evidence to support any proven association between short-term PPI use and dementia.[7] The authors also suggested that in patients with valid indications, long-term PPI use should not be avoided for concerns about dementia risk, and PPIs should be given at the lowest effective dose. Clostridium difficile infection Meta-analyses of predominantly case–control and cohort studies suggest that PPI use increases the risk of CDI owing to its inhibition of gastric acid secretion, with a mild to moderate causal association.[8]Clostridium difficile infection should be considered in patients on long-term PPIs who present with prolonged diarrhoea. Proton pump inhibitors have also been found to increase the risk of recurrence of CDI in the elderly above the age of 75 (HR 1.5, 95% CI 1.1–2.0). If indicated, PPIs should be used with caution and at the lowest effective dose in patients with a history of CDI. Pneumonia Gastric acid suppression and elevation of gastric pH alter the gut and oropharyngeal bacterial flora, and they have been postulated to be responsible for the possible association between PPI use and the development of pneumonia. Results from multiple studies are conflicting, with one meta-analysis (33 studies, 226,769 cases of pneumonia) showing a pooled risk of 1.49 (95% CI 1.16–1.92),[9] and other studies reporting no association (adjusted OR 1.05, 95% CI 0.89–1.25).[10] As with most reported side effects, no causal association has been identified. There are no specific recommendations that address PPI use and the risk of developing pneumonia. Complications and decompensation in liver cirrhosis Current evidence supporting the association of PPI use with complications and decompensation in liver cirrhosis is not supported by results from well-designed prospective studies. Once again, multiple observational studies have yielded conflicting results. Locally, a retrospective study evaluating 295 patients with decompensated cirrhosis (238 PPI users) showed that PPI users had higher mortality (adjusted HR 2.10, 95% CI 1.20–3.67), especially with longer duration of PPI use.[11] Given the potential increased risk of spontaneous bacterial peritonitis, liver decompensation and death, PPIs should be used only in the presence of an evidence-based indication. The lowest effective dose should be used for the shortest possible time. Patients with decompensated cirrhosis should also be referred to a gastroenterologist for long-term management. Cardiovascular events Concerns regarding PPI use and increased risk of cardiovascular events arise from the potential interaction with thienopyridine derivatives such as clopidogrel. Randomised controlled studies and meta-analyses have been performed to address the clinical impact of this interaction. The COGENT study is a placebo-controlled randomised trial that aimed to study the effect of omeprazole in 3,873 patients who required clopidogrel. It is the only study that is specifically designed to address the potential for PPIs to reduce the efficacy of clopidogrel.[12] The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularisation or stroke. The study reported no apparent cardiovascular interaction between the two drugs. There was, however, increased risk of upper gastrointestinal bleed among patients who did not receive omeprazole. A large meta-analysis published in 2013 reviewed a total of 23 studies with 222,311 patients.[13] This study found increased pooled estimates of cardiovascular risk in patients using PPIs and clopidogrel, and also in patients on PPIs alone. The authors concluded that there remains uncertainty regarding the clinical validity or relevance of the hypothesised PPI–clopidogrel interaction. This remains a topic for further research and more evidence is needed, given the conflicting evidence between observational studies and randomised controlled trials. There are no recommendations made against PPI use for patients on thienopyridine derivatives. WHAT ARE THE INDICATIONS FOR LONG-TERM PROTON PUMP INHIBITOR THERAPY? The indications for long-term PPI therapy,[14] based on review of the existing literature, are shown in Figure 1. Patients who fulfill these indications should be given the lowest effective dose to minimise potential side effects.Figure 1: Flowchart shows the process of deprescribing proton pump inhibitors.WHAT CAN I DO IN MY PRACTICE? Most data on the side effects related to long-term PPI use demonstrate correlation without a strong evidence of causality. In the presence of an indication for long-term PPI therapy, the benefits of PPI therapy should be considered and PPI should continue to be prescribed.[15] However, physicians should review the indications of all chronic medications during each patient encounter. Deprescribing PPIs involves dose reduction, cessation or switch to ‘on-demand’ dosing, with the guiding principle of using PPIs at the lowest effective dose for the shortest possible time. A flowchart to guide the decision-making process of deprescribing PPIs is shown in Figure 1. TAKE HOME MESSAGES A large proportion of patients are on long-term PPIs without appropriate evidence-based indications. Proton pump inhibitors have been associated with numerous side effects, with evidence (overall very low to low quality) derived from observational studies. Although causality between major side effects and PPIs has not been proven, long-term PPIs should be used only in the presence of evidence-based indications. If indicated, PPIs should be used at the lowest effective dose for the shortest possible time. Physicians should review indications for PPI use and actively deprescribe PPIs if possible. Deprescribing PPIs involved dose reduction, cessation or switch to ‘on-demand’ dosing. Closing Vignette You diagnosed Madam Tan with functional dyspepsia. The dose of omeprazole was reduced to 20 mg OM, to be taken when required. You planned to stop PPI therapy on resolution of her dyspepsia, as she should not be on long-term PPI therapy. Recurrence or persistence of symptoms may prompt further evaluation, especially in the presence of alarm symptoms, such as unintended weight loss, gastrointestinal bleeding, iron deficiency anaemia, dysphagia, odynophagia, persistent vomiting and nocturnal symptoms affecting sleep.Financial support and sponsorship Nil. Conflicts of interest Puar THK and How CH are members of the SMJ Editorial Board, and were thus not involved in the peer review and publication decisions of this article. SMC CATEGORY 3B CME PROGRAMME Online Quiz: https://www.sma.org.sg/cme-programme Deadline for submission: 6 pm, 06 Sep 2023" @default.
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• W4385477674 date "2023-07-31" @default.
• W4385477674 modified "2023-10-14" @default.
• W4385477674 title "Deprescribing proton pump inhibitors" @default.
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