PPIs and probiotics

PPIs and probiotics

How safe are PPIs, and when should I get my patients off of them? Ankur Jain, MD, FACG Assistant Clinical Professor of Medicine, JABSOM Governor of Hawaii, American College of Gastroenterology 10/14/19 Objectives Review appropriate indications for PPIs and recommended treatment durations Present most convincing medical literature evaluating long-term safety of PPIs Discuss strategies for deprescribing PPIs for patients who no longer

require therapy Introduce best practices for long-term PPI use Financial disclosures No disclosures to report Question#1 Which of the following is the most appropriate duration of PPI treatment for uncomplicated peptic ulcer disease? Question#1 A. 2-4 weeks B. 6-8 weeks C. 8-12 weeks

D. Greater than 1 year E. None, treatment is not indicated Question#1 B. 6-8 weeks Question#2 Which of the following is the most appropriate duration of PPI treatment for functional (non-ulcer) dyspepsia? Question#2 A. 2-4 weeks B. 6-8 weeks C. 8-12 weeks

D. Greater than 1 year E. None, treatment is not indicated Question#2 A. 2-4 weeks Question#3 Which of the following is the most appropriate duration of PPI treatment for reflux esophagitis? Question#3 A. 2-4 weeks B. 6-8 weeks C. 8-12 weeks

D. Greater than 1 year E. None, treatment is not indicated Question#3 C. 8-12 weeks Question#4 Which of the following is NOT an indication for long-term (ie. greater than 1 year) PPI use? Question#4 A. Patients with uncomplicated GERD who respond to short-term therapy B. Patients with Barretts esophagus and symptomatic GERD

C. Patients with recurrent PUD despite negative work-up for secondary causes D. Patients at high risk for ulcer-related bleeding from NSAIDs who continue to take NSAIDs E. All of the above are indications for long-term PPI use Question#4 A. Patients with uncomplicated GERD who respond to short-term therapy Question#5 Which of the following is NOT an indication for high dose (ie. BID dosing) of PPI?

Question#5 A. Persistent/severe esophagitis B. Complicated/refractory PUD C. Known hypersecretory states such as Zollinger-Ellison syndrome (ZES) D. Functional dyspepsia not responding to once daily PPI E. Abnormal pH test already on once daily PPI Question#5 D. Functional dyspepsia not responding to once daily PPI Outline Background Mechanism of action

Dosing and administration Indications Adverse reactions Deprescribing Best practice recommendations Background Proton pump inhibitors (PPIs) were first introduced in 1980s Represent major breakthrough in mgmt of acid-related disease Now among most widely prescribed drugs, second to only statins In 2013, over $8.4 billion spent in US and over $13 billion worldwide 810% of adults were prescribed a PPI in past 30 days 13% of adults use PPI at least twice weekly People over 60 years of age 3.5 times more likely to use PPIs

Available PPI formulations Omeprazole (Prilosec) (1988) Pantoprazole (Protonix) (1994) Lansoprazole (Prevacid) (1995) Rabeprazole (Aciphex) (1999) Esomeprazole (Nexium) (2001) Lanso/naprox (NepraPAC) (2003) Ome/Na bicarb (Zegerid) (2004) Dexlansoprazole (Dexilant) (2009) Eso/ibuprofen (Vimovo) (2010) Available PPI formulations

Top proton pump inhibitors based on U.S. revenue millions of U.S. dollars in 2013 Mechanism of action Gastric acid produced by gastric H+/K+ ATPase (proton pump) kills ingested microorganisms limits bacterial growth in stomach (other than H. pylori) prevents intestinal infections such as C. difficile

facilitates digestion of protein and absorption of iron, calcium, and B12 allows absorption of basic drugs including metoprolol and allopurinol Regulation of acid secretion relies on: Gastrin (stimulated by food) Acetylcholine (stimulated by vagus nerve) Histamine (stimulated by gastrin and acetylcholine) Mechanism of action Acid can also have caustic effects on the lining of the gastrointestinal mucosa causing symptoms and injury including esophagitis and ulcers Normal gastroduodenal mucosa protects itself from harmful effects of acid through various defensive and healing mechanisms including: Mucus

Prostaglandin Bicarbonate secretion When these mechanisms fail acid related injury can occur Medications can help to neutralize acid or suppress acid production Mechanism of action Acid-suppressing medications include: Antacids such as sodium bicarbonate, magnesium or aluminum hydroxide, calcium carbonate, and bismuth subsalicylate Histamine type 2 (H2) blockers Proton pump inhibitors (PPI) These medications

control various different upper GI symptoms including GERD and dyspepsia prevent ulcers from forming in setting of non-steroidals and h pylori infection allow healing of existing ulcers in the esophagus, stomach, and duodenum Mechanism of action Antacids generally work by simple neutralization of acid H2 blockers bind to parietal cell H2 receptors, blocking histamine released by ECL cells PPIs irreversibly bind to and block active proton pumps in the gastric oxyntic mucosa, inhibiting acid production from all pathways Results in profound reduction in basal and stimulated gastric acid output, maintaining intragastric pH at high levels Allows for consistent prevention and healing of esophagitis and peptic ulcer disease and more rapid control of symptoms

Mechanism of action Dosing and administration Most PPIs are encapsulated or enterically coated (EC) to protect the medication against degradation by gastric acid Opening capsule may leave granules vulnerable to degradation, premature activation in presence of acid, and decreased efficacy All EC PPIs can be administered via NG tubes, while omeprazole and lansoprazole are also effectively administered via G-tube For pts with J-tubes, only omeprazole has been found to be effective Pantoprazole, esomeprazole, and lansoprazole available as liquid/IV Dosing and administration

Drug Omeprazole Dosages (mg) Capsule or tablet 10, 20, 40 Capsule Liquid or suspension IV No Yes Generic Yes

OTC Yes Pantoprazole 20, 40 Tablet Yes Yes Yes

No Lansoprazole 15, 30 Capsule Yes Yes Yes

Yes Rabeprazole 20 Tablet No No Yes

No Esomeprazole 20, 40 Capsule Yes Yes Yes

Yes Dexlansoprazole 30, 60 Capsule No No No

No Omeprazole 20mg Pantoprazole 40mg Equivalent dosing of various PPIs Lansoprazole 15mg Rabeprazole 20mg Esomeprazole 20mg Dexlansoprazole 30mg Dosing and administration

PPIs work best on empty stomach, at least 30 minutes before a meal Half-life of PPIs is 6090 min, but acid inhibition lasts up to 24 hrs Single dose of PPI does not inhibit all active pumps Acid secretion inhibited with subsequent PPI doses, up to 5-7 days Steady-state inhibition achieved more rapidly with twice daily dosing Alternate PPIs can be considered due to cost or intolerance No evidence that one PPI is more effective than another FDA-approved indications Treatment of gastroesophageal reflux disease (GERD) Healing of erosive esophagitis (EE) Maintenance of healed EE Risk reduction for gastric ulcer (GU) associated with nonsteroidal antiinflammatory drugs (NSAIDs) Short-term treatment and maintenance of duodenal ulcers (DUs)

Helicobacter pylori (H. pylori) eradication to reduce risk of DU recurrence, in combination with antibiotics Pathological hypersecretory conditions, including ZES FDA-approved indications Indication Omeprazole Pantoprazole Lansoprazole Rabeprazole

Esomeprazole Dexlansoprazole Nonerosive reflux disease Yes No Yes Yes

Yes Yes Erosive esophagitis-healing Yes Yes Yes Yes

Yes Yes Erosive esophagitis-maintenance Yes Yes Yes Yes

Yes Yes Gastric ulcer-healing Yes No Yes No

No No NSAID induced ulcer-healing No No Yes No

No No NSAID induced ulcer-prophylaxis No No Yes No

Yes No Duodenal ulcer-healing Yes No Yes Yes

No No Duodenal ulcer-maintenance No No Yes No

No No Dual therapy Yes No Yes No

No No Triple therapy Yes No Yes Yes

Yes No Zollinger-Ellison syndrome Yes Yes Yes Yes

Yes No GERD Peptic Ulcer Disease Treatment of H. pylori Erosive esophagitis and Barretts esophagus

Peptic ulcer disease Indications for long-term PPI therapy Definite indications Treatment of recurrent erosive esophagitis for prevention of relapse Prevention of progression of Barretts esophagus in symptomatic patients Treatment of PPI-responsive esophageal eosinophilia Prevention of PUD and its complications in chronic NSAID users

Treatment of recurrent PUD after negative work-up for secondary causes Not indicated Endoscopy-negative reflux disease (NERD) responding to short-term therapy Symptoms due to LPR/atypical manifestations of GERD Functional (non-ulcer) dyspepsia responding to short course of PPI Indications for BID or higher dosing Definite indications

Persistent/severe esophagitis Abnormal pH test (persistent GERD) already on once daily PPI Symptoms due to LPR/atypical manifestations of GERD Complicated/refractory peptic ulcer disease (PUD) Known hypersecretory states such as Zollinger-Ellison syndrome (ZES) Not indicated Uncomplicated GERD Simple PUD Functional dyspepsia not responding to once daily PPI pH monitoring

pH monitoring Kleiman and others retrospectively reviewed type of symptoms and duration of PPI for 100 pts who later underwent pH monitoring In a cost effectiveness study, they subtracted cost of unnecessary PPIs from cost of pH monitoring in pts with normal pH Cost model showed pH monitoring after 8-week PPI trial would have saved from $1966 to $7285 per patient over 10 yrs Authors concluded that early referral for pH monitoring saves $6600 per patient over 10 yrs Cutting down unnecessary PPI use not only helps decrease costs but may also decrease potential risks of long-term exposure Adverse reactions PPIs are generally well tolerated; acute reactions occur only 1-3%

Headaches, dizziness Abdominal pain, nausea, vomiting Flatulence, diarrhea Drug-drug interactions have been reported with certain PPIs Most PPIs are pregnancy category B (omeprazole is category C), but there are no recommendations for use in breast-feeding Over last 20 years, a large number of articles have been published regarding safety of long-term use, leading to several FDA notifications Potential long-term safety considerations AIN CKD

Dementia Osteoporosis/bone fractures Acute MI Interaction with clopidogrel SBBO C. difficile-associated diarrhea Other enteric infections Microscopic colitis Colon cancer SBP/mortality in cirrhosis Pneumonia/URI Iron and vitamin B12 deficiency Hypomagnesemia

Mortality after PEG insertion Gastric carcinoid tumors/polyps Interaction with methotrexate Proposed mechanisms for PPI complications Less gastric acid production results in hypergastrinemia and changes in environment of stomach and lower bowel May result in immunosuppression with overgrowth of gastric bacteria and altered intestinal normal flora May affect how Fe, Ca, and minerals like B12 are absorbed May also affect how other drugs are metabolized and absorbed May lead to trophic changes of the stomach and colon

Direct metabolic interaction with hepatic cytochrome p450, especially omeprazole which is a p450 inducer Proposed mechanisms for PPI complications Kidney Recurrent AIN Brain a) Decreased gastric acidity leading to B12 def b) Beta-amyloid deposition Bone a) Decreased gastric acidity leading to Ca def b) Hypergastrinemia leading to hyperparathyroidism Heart a) CYP450/CYP2C19 induction inhibiting clopidogrel activation

b) Increased asymmetric dimethylarginine (ADMA) leading to reduced endothelial nitric oxide resulting in thrombosis Colon a) Decreased gastric acidity altering normal intestinal flora Proposed mechanisms for PPI complications Liver a) Decreased gastric acidity altering gut microbiota Decreased gastric acidity leading to B12 deficiency Lungs a) Decreased gastric acidity leading to overgrowth of gastric bacteria b) Antineutrophilic effect of PPIs Muscle a) Decreased gastric acidity leading to Fe and B12 def b) CYP3A4 enzyme inhibition Blood Decreased gastric acidity leading to Fe and B12 def

Stomach a) Decreased gastric acidity leading to overgrowth of gastric bacteria b) Acid suppression induced parietal cell hyperplasia b) Proposed mechanisms for PPI complications FDA drug safety communications 11/17/09: Update to the labeling of clopidogrel bisulfate to alert healthcare professionals about a drug interaction with omeprazole 5/25/10: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors

3/2/11: Low magnesium levels can be associated with long-term use of proton pump inhibitor drugs 2/8/12: Clostridium difficile associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors Interaction with clopidogrel Some data suggest decreased activation of clopidogrel in omeprazole users Both drugs share hepatic CYP450 and CYP2C19 metabolism 2012 nonrandomized subgroup analysis of PLATO trial Use of PPI was associated with higher rate of CV events in those taking either clopidogrel or ticagrelor 2015 meta-analysis of six observational studies evaluating composite outcome of death, MI, or CVA with various different PPIs:

pantoprazole (HR 1.38, 95% CI 1.12-1.70) lansoprazole (HR 1.29, 95% CI 1.09-1.52) esomeprazole (HR 1.27, 95% CI 1.02-1.58) omeprazole (HR 1.16, 95% CI 0.93-1.44) Interaction with clopidogrel Only large scale RCT comparing omeprazole to placebo in clopidogrel users (COGENT trial) published in NEJM in 2010 NO significant difference in CV events when two were combined (HR 0.99; 95% CI 0.68-1.44) Significant reduction in gastrointestinal events (HR 0.34; 95% CI 0.18-0.63) Subsequent systematic review of published data concluded that adverse effect of PPI use with clopidogrel cannot be substantiated

Risks and benefits of clopidogrel and concomitant PPI therapy need to be individualized based on indication for PPI use Prophylactic PPI should be considered for pts taking clopidogrel who have high risk of PUD (similar to daily ASA users) Fracture risk Long-term PPI use has been associated with risk of osteoporosis and decreased bone mineral density (BMD), with 35% risk of fractures Calcium serves an important role in bone health and formation as key component of hydroxyapatite, which is main element of bone PPI-induced fractures may occur because some dietary calcium absorption is dependent upon acidic environment in GI tract Hypochlorhydria reduces absorption of water insoluble calcium (eg. calcium carbonate), which can be overcome by consuming a meal

Absorption of water-soluble calcium salts (eg. calcium citrate) or calcium in dairy are not impacted by PPI-induced hypochlorhydria This reduction in calcium absorption can augment osteoclastic activity, increasing bone loss and further reducing BMD Fracture risk Some early studies with omeprazole showed that fractional absorption of calcium was reduced in postmenopausal women Large prospective cohort study from 2010 Arch Intern Med PPI associated with increased risk of vertebral (HR 1.47, 95% CI 1.18-1.82), wrist, and total fractures Subsequent 2011 analysis, concurrent use of PPIs and alendronate

associated with loss of protection against fracture (39 versus 19%) 2011 Am J Med meta-analyses of 11 case-control and cohort studies RR of hip, spine, and any-site fractures was 1.30, 1.56, and 1.16, with PPI use Risk was highest in long-term users (>1 year) of high-dose PPI therapy Fracture risk These studies did demonstrate association between long-term PPI use and risk of fractures but contained numerous confounders In one analysis from 2012, fracture risk in PPI users was confined to pts with at least one other risk factor: current or former smokers sedentary lifestyle use of certain medications (e.g., HCTZ, HRT, CS)

Targownik et al. also found in 2012 that pts using PPIs were older (66.3 vs. 60.9 years; P <.001) with higher BMI (28.3 vs. 26.9; P <.001) Fracture risk Another large prospective cohort study from 2012 showed chronic PPI use over 10 years not associated with accelerated BMD decline Other studies have similarly found no decrease in BMD in PPI users Although association between PPI use and bone fracture is plausible, causality not yet established In March 2011, FDA concluded that OTC PPI products do not warrant label changes to include warnings of fracture risk 2013 ACG guidelines on GERD state that existing osteoporosis is not a contraindication to PPI therapy, unless other risk factors exist

Low serum magnesium levels All PPIs are associated with decreased Mg absorption Mechanism for reduced absorption may be inhibition of transient receptor potential melastatin-6 (TRPM6) and TRPM7 channels Hypomagnesemia occurred in approximately 1% of pts taking PPIs according to the FDAs Adverse Reporting System Mean time is 5.5 yrs, but cases have been reported within 1 yr 2015 meta-analysis of 9 observational studies with 109,798 pts PPI use had RR 1.43 (95% CI, 1.08-1.88) for low Mg Low serum magnesium levels Symptoms include palpitations, tetany, convulsions, and weakness Clinical manifestations include neuromuscular excitability (tremor, tetany, seizures) and hypotension

Severe PPI-induced hypomagnesemia has also been associated with arrhythmias due to QT interval prolongation and torsades de pointes It is potentially fatal Pts who present with clinically significant hypomagnesemia may require Mg replacement and discontinuation of PPI therapy Hypomagnesemia generally resolves after discontinuation but recurs soon after PPI is re-challenged Low serum magnesium levels Hypomagnesemia is more common in older pts taking a PPI (mean age 64.4 yrs) and pts with renal failure Concurrent use of medications that decrease Mg also increases risk of significant hypomagnesemia Danziger et al. reported that pts who take a PPI with a diuretic have

nearly 55% greater risk of hypomagnesemia than with PPI alone FDA suggests obtaining Mg levels prior to initiation of therapy and periodically thereafter although AGA advises against routine testing Association with C. difficile PPI use has also been associated with increased risk of initial and recurrent C. difficile infection (CDI) Gastric acid is a defense mechanism against enteric bacteria Increased gastric pH may allow colonization of opportunistic microbes Risk of CDI appears to be greater with PPIs as compared to H2 receptor antagonists and other antacids Association with C. difficile 2005 retrospective study

Pts taking PPIs had HR of 2.9 (95% CI, 2.4-3.4) for developing C. difficile 75% of pts with reported cases of C. difficile were over age 65 Pts who received PPI during treatment of C. difficile were 42% (95% CI, 1.111.82) more likely to have recurrent infection after finishing therapy 2012 meta-analysis of 29 studies of pts with CDI PPIs increased risk of CDI (pooled OR = 2.15; 95% CI 1.81 2.55) 2017 meta-analysis of 50 observational studies Also noted that PPI use increased risk of CDI (RR 1.3; 95% CI 1.1-14) Association with C. difficile In a 2010 study Linsky et al. determined whether patients with recurrent CDI received a PPI within 14 days of initial infection HR for pts on PPIs during treatment was 1.42 (95% CI 1.11-1.82)

For pts over age 80, HR increased to 1.86 (95% CI 1.15-3.01) 2017 meta-analysis of 16 studies that included 1525 pts Acid therapy had OR 1.5 (95% CI 1.2-1.9) for recurrent infection In adjusted analysis from 9 studies, PPI use was increased even after controlling for age and other conditions (OR 1.4; 95% CI, 1.1-1.8) 2013 ACG guidelines on GERD recommend use of PPIs with caution in pts with a risk of C difficile infections (CDI) Latest study Safety of Proton Pump Inhibitors Based on a Large, Multi-year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin Moayyedi, et al. Gastroenterology. Sept 2019. 157 (3): 682-691.

Large placebo-controlled RCT, part of the original COMPASS trial 17,598 individuals received pantoprazole or placebo, and were followed for up to 3 years Primary outcome was protection against GI bleeding while safety analysis was conducted as secondary outcome Pantoprazole was not associated with any adverse event when used for 3 years, with possible exception of an increased risk of enteric infections Moayyedi reports receiving research funding from Allergan and Takeda Figure 2 Gastroenterology 2019 157, 682-691.e2DOI: (10.1053/j.gastro.2019.05.056) Copyright 2019 AGA Institute Terms and Conditions

Figure 3 Gastroenterology 2019 157, 682-691.e2DOI: (10.1053/j.gastro.2019.05.056) Copyright 2019 AGA Institute Terms and Conditions Potential long term safety considerations Potential Adverse Effect Relative Risk Reference for Risk Estimate

Reference for Incidence Estimate Absolute Excess Risk Chronic kidney disease 10% to 20% increase Lazarus et al48 Lazarus et al48

0.1% to 0.3% per patient/y Dementia 4% to 80% increase Haenisch et al90 Haenisch et al90 .07% to 1.5% per patient/y Bone fracture

30% to 4-fold increase Yang et al27 Yang et al27 0.1% to 0.5% per patient/y Myocardial infarction No association in RCTs ---

--- --- SIBO 2-fold to 8-fold increase Lo et al91 None available Unable to calculate

Enteric infections 2-fold to 6-fold increase Bavishi et al26 Crim et al92 .03% to 0.2% per patient/y SBP 50% to 3-fold increase

Xu et al93 Fernandez et al94 3% to 16% per patient/y C difficile infection No risk to 3-fold increase Furuya et al95 Lessa et al96

0% to .09% per patient/y Pneumonia No association in RCTs --- --- --- Micronutrient deficiencies

60% to 70% increase Lam et al97 Bailey et al98 0.3% to 0.4% per patient/y GI malignancies No association in RCTs ---

--- --- Interaction with clopidogrel No association in RCTs Evidence for Adverse Events Related to Acid Inhibition Evidence for Adverse Events Unrelated to Acid Inhibition

Keep calm and carry on There is currently inadequate evidence to establish causal relationships between PPI therapy and proposed associations Safety reviews to date assess evidence as "low" or "very low quality since data only demonstrates modest association and not causality Most reports are retrospective case control studies (cross-sectional) limited by channeling bias and confounding factors Only available RCTs have shown no risk of MI, PNA, or GI malignancy, and no interaction with clopidogrel, with slight inc enteric infx When used appropriately, benefits of PPIs outweigh risks, but when used inappropriately, even modest risks become important Deprescribing If a patient does not have a definite indication for long-term PPI

therapy, what strategies can we use to take them off of them? Options include: Stepping down to a lower dose or intermittent/on-demand treatment regimen Discontinuing PPIs outright, either suddenly or gradually Substituting PPI with less potent form of acid inhibition (ie. H2 blocker) Step-down regimens Initial goal should be to take patients off high dose PPI therapy if there is no clear indication Inadomi et al. prospectively demonstrated that 80% of pts could be stepped down to standard dosing without recurrent symptoms Pts already on low dose PPI may be harder to wean off Theoretical risk of rebound acid hypersecretion with sudden

discontinuation resulting in symptom recurrence Phenomenon was seen in studies by Reimer et al. and Niklasson et al. Total discontinuation of PPIs Studies by Boghossian et al. and Hansen et al. also suggest loss of symptom control with intermittent dosing or switching to H2 blocker For these patients, another option is to taper their PPI gradually, initially decreasing use to every 2 or 3 days over several weeks Inadomi et al. found that 60% of PPI users discontinued over 2 wks were asymptomatic on no or OTC antacids over the following yr Deprescribing Barbara Farrell et al. from University of Ottawa published an evidence-based guideline in Canadian Family Physician in 2017

For adults older than 18 yrs with upper GI symptoms who received PPIs for minimum of 4 weeks and experienced symptom resolution Clinicians should either reduce the daily dose of PPI or stop the drug and switch patient to on-demand PPI use "strong evidence" Clinicians may consider stepping down to histamine-2 receptor antagonist therapy "weak evidence" Deprescribing AGA Best Practices for Long-Term PPI use Patients with GERD and acid-related complications should take PPI for short-term healing, maintenance, and long-term symptom control Patients with uncomplicated GERD who respond to short-term PPIs

should subsequently attempt to stop or reduce them Patients with Barretts esophagus and symptomatic GERD should take a long-term PPI Asymptomatic patients with Barretts esophagus should consider a long-term PPI Patients at high risk for ulcer-related bleeding from NSAIDs should take a PPI if they continue to take NSAIDs AGA Best Practices for Long-Term PPI use Specific PPI formulations should not be selected based on risks Dose of long-term PPIs should be periodically reevaluated so that lowest effective dose can be prescribed to manage the condition Patients who cannot reduce PPIs should consider ambulatory

pH/impedance monitoring before committing to lifelong PPIs Long-term PPI users should not routinely: screen or monitor bone mineral density, serum creatinine, magnesium, or B12 raise their intake of calcium, B12, or magnesium beyond Recommended Dietary Allowance use probiotics to prevent infection Final thoughts After what duration of PPI therapy are patients at risk for complications? Are there specific populations at higher risk for these complications? Do certain PPI formulations carry higher risk of complications than others?

Summary PPIs are highly efficacious acid-suppressing medications that block all three acid-producing pathways PPIs work best on an empty stomach, at least 30 minutes before a meal, and require at least 5-7 days to achieve a steady state PPIs should be prescribed only when clinically appropriate, at lowest effective dose for proven indication, for recommended treatment duration Avoid chronic therapy after a negative work-up, and avoid dose escalation in people unresponsive to initial empiric therapy When long term use is needed, use only appropriate maintenance dose and consider on-demand PPIs or drug holidays Any questions?

References ACG Website: http://universe-syllabi.gi.org/acg2011_16_slides.pdf AJG April 2018; 113(4): 519-528 Discontinuing Long-Term PPI Therapy: Why, With Whom, and How Aliment Pharmacol Ther. Torvinen-Kiiskinen S, et al. 2018 BMC Medicine 2016 14: 179 Effective and safe proton pump inhibitor therapy in acid-related diseases A position paper addressing benefits and potential harms of acid suppression BMJ 2017 7:e015735 Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans CAG/CASL Postgraduate Course 2016: Safety Monitoring; https://www.cagacg.org/images/cddw/safety-monitoring_ppi-risks_leontiadis.pdf References

Canadian Family Physician May 2017; 63(5): 354-364 Deprescribing proton pump inhibitors Evidence-based clinical practice guideline CMS Website: https://www.cms.gov/.../Downloads/ppi-adult-factsheet.pdf Digestive Disease Week (DDW) 2013. Abstract 201. Presented May 19, 2013. Early pH study in GERD may save money Gastroenterology March 2017; 152(4): 706-715 The Risks and Benefits of Long-term Use of Proton Pump Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association Gastroenterology July 2017; 153(1): 35-48 Complications of Proton Pump Inhibitor Therapy References Gut and Liver 2017; 11(1): 27-37 https://doi.org/10.5009/gnl15502 25 Years of Proton Pump Inhibitors: A Comprehensive Review

Gut Apr 2018. Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants. Medscape website: https://www.medscape.org/viewarticle/500638_4. Pharmacology of PPIs -- Therapeutic Implications: Pharmacology and Mechanism of Action NEJM 2010; 363 (2): 1909. Clopidogrel with or without omeprazole in coronary artery disease. Pharmacology of PPIs -- Therapeutic Implications: Pharmacology and Mechanism of Action References Therapeutic Advances in Drug Safety 2019, Vol.10: 113. The risks of longterm use of proton pump inhibitors: a critical review US Pharm 2013; 38(12): 38-42. Long-Term Consequences of Chronic Proton Pump Inhibitor Use

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